Proteinuric renal disease

Gene: CD2AP

Green List (high evidence)

Comment on list classification: There are at least 4 unrelated cases reported with homozygous variants in CD2AP and Focal segmental glomerulosclerosis / nephropathy (PMIDs: 17713465, 30348286, 30612599, 36964972). Several reported heterozygous variants have high allele frequencies in the general population, including in homozygosity, and their pathogenicity is disputed (PMIDs:19131354; 26997877) . However, there are at least 3 unrelated individuals reported with FSGS and heterozygous variants in CD2AP that are sufficiently rare (12764198; 19131354; 34408996). This gene-disease relationship is also supported by functional studies in mice (PMIDs: 10514378; 30612599). Based on the available evidence, this gene should be rated Green for Proteinuric renal disease, with MOI set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.

Created: 20 Oct 2025, 1:12 p.m. | Last Modified: 21 Oct 2025, 2:04 p.m.

Panel Version: 5.5

Biallelic cases:
Two articles reviewed previously by Eleanor Williams report 2 unrelated cases with homozygous nonsense variants in CD2AP and Focal segmental glomerulosclerosis (PMID:17713465 - Löwik et al 2007 & PMID: 30612599 - Takano et al 2019). Extra case reports:

PMID: 30348286 Gribouval O, et al., 2018,
Male individual homozygous for NM_012120.3 (CD2AP):c.634C>T (p.Arg212Ter) Focal segmental glomerulosclerosis - age of onset 24yo; eGFR at onset: 12 Albuminemia g/l: 28 Proteinuria g/g: 3.6; End stage renal disease at 25yo. Method: NGS panel of 35 genes.

PMID: 36964972 Gorukmez O, et al., 2023
23 year old male with a homozygous variant in CD2AP who presented with nephropathy. Variant: NM_012120.3 (CD2AP):c.1742del (p.Asn581IlefsTer17). Method: clinical WES.

Monoallelic cases:

PMID: 12764198 Kim et al 2003
Screened 30 African-Americans with idiopathic FSGS and 15 African-Americans with HIV-associated FSGS for changes in CD2AP. PCR sequencing of CD2AP only. Variant c.730-1_730delinsCT was found in 2 patients with primary FSGS; CD2AP protein levels were lower in these patients. Variant not present in gnomAD v4. CD2AP+/- mice showed glomerular abnormalities at 9 months of age but not proteinuria.

PMID: 19131354 Gigante et al., 2009
3 unrelated Italian patients with idiopathic nephrotic syndrome, heterozygous for one mutation each:
c.902A>T, (p.Lys301Met) - total AF in gnomAD v.4 = 0.0001904 including 5 homozygotes; not likely to be disease causing.
c.1120A>G, (p.Thr374Ala) - total AF in gnomAD v.4 = 0.005488 including 48 homozygotes; not likely to be disease causing.
c.1569AGA[2] (p.Glu525del) - total AF in gnomD v.4 = 0.0003639, no homozygotes reported.

PMID: 25501161 Feng et al., 2014
Patient 2- presented nephrotic syndrome at 8yo - steroid resistant. Renal biopsy showed MCNS; heterozygous for a CD2AP mutation, IVS7-135G>A (intron 7).
Patient 25 - FSGS onset at 4.5yrs - steroid resistant; went into remission after receiving cyclosporin A. Het for IVS13-137G>A (intron 13).
Method: sequenced NPHS1, NPHS2, CD2AP, and WT1 only.

PMID: 26997877 Tsvetkov et al., 2016
Male patient, German ancestry, presented with a nephrotic syndrome (proteinuria >3.5 g/day) at 28yo; kidney biopsy confirmed FSGS diagnosis; heterozygous for c.1120A>G, p.(Thr374Ala) in CD2AP - variant too common in population to cause disease. Mother and brother also have kidney disease, not genotyped. Seq method: sequencing of exons only of the following genes: TRPC6, ACTN4, WT1, CD2AP, and INF2.

PMID: 34408996 Liu et al., 2021
Chinese family of four generations with unexplained proteinuria. The proband IV-1, a 12-year-old boy, had steroid resistant high proteinuria (2+). He was reported as heterozygous for c.1734_1735insG, p.Lys579Glufs*7 in CD2AP - AF in gnomAD v4: 6.198e-7. Seq method: WES. Variant shown to segregate with disease in this family. 10 other possibly pathogenic variants detected but not associated with kidney disease.

CD2AP is classified Definitive for AR 'focal segmental glomerulosclerosis 3, susceptibility to', and Moderate for AD 'inherited focal segmental glomerulosclerosis' in ClinGen (curated by the Glomerulopathy Gene Curation Expert Panel in 2024).
This gene is associated with Glomerulosclerosis, focal segmental, 3, 607832 in OMIM (accessed 20th Oct 2025) - no mode of inheritance listed.

Created: 20 Oct 2025, 12:47 p.m. | Last Modified: 21 Oct 2025, 1:55 p.m.

Panel Version: 5.5

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Glomerulosclerosis, focal segmental, 3, OMIM:607832; focal segmental glomerulosclerosis 3, susceptibility to, MONDO:0011917

Publications

• 10514378
• 12764198
• 17713465
• 19131354
• 25501161
• 26997877
• 30348286
• 30612599
• 34408996
• 36964972

I don't know

Two unrelated families reported with homozygous variants in this gene reported; mouse model supports pathogenicity, suggest promoting to Amber.

Created: 9 Jan 2020, 3:30 a.m. | Last Modified: 9 Jan 2020, 3:30 a.m.

Panel Version: 2.0

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Glomerulosclerosis, focal segmental, 3 #607832

Publications

• 17713465
• 30612599

I don't know

Comment on phenotypes: OMIM phenotype accessed on 21st October 2025

Created: 21 Oct 2025, 9:59 a.m. | Last Modified: 21 Oct 2025, 9:59 a.m.

Panel Version: 5.5

Associated with Glomerulosclerosis, focal segmental, 3 #607832 in OMIM (no inheritance given)

Mouse knockout model supports renal involvement. 2 cases with heterozgous variants and FSGS but only CD2AP looked at. Two familial cases of homozygous variants (in one only CD2AP screened) and FSGS.

PMID: 10514378 - Shih et al 1999 - In CD2AP-deficient mice, immune function was compromised, but the mice died at 6 to 7 weeks of age from renal failure. In the kidney, CD2AP was expressed primarily in glomerular epithelial cells.

PMID: 12764198 - Kim et al 2003 - CD2AP+/- mice showed glomerular abnormalities at 9 months of age but not proteinuria. Screened 30 African-Americans with idiopathic FSGS and 15 African-Americans with HIV-associated FSGS for changes in CD2AP. One variant, predicted to affect the splice acceptor of exon 7 in one allele, was found in 2 patients with primary FSGS and expression of the protein was lower in these patients.

PMID:17713465 - Löwik et al 2007 - report a homozygous variant in a proband with primary Focal segmental glomerulosclerosis, from a consanguineous family of Mediterranean ancestry. A homozygous c1834 C>T (R612Stop) variant was found. Both parents were proven to be heterozygous for this mutation. An immunoblot shows no CD2AP expression in the patient carrying the R612Stop mutation homozygously

PMID: 30612599 - Takano et al 2019 - Using WES, they identified a homozygous frame-shift mutation in CD2AP (p.S198fs) in three siblings born of consanguineous parents who developed childhood-onset FSGS and end stage renal disease. When the same frameshift mutation was introduced in mice by gene editing, the mice developed FSGS and kidney failure. (Abstract only accessed).

Created: 30 Jan 2020, 1:58 p.m. | Last Modified: 21 Oct 2025, 10:04 a.m.

Panel Version: 5.5

This gene was part of an initial gene list collated by Elizabeth Watson, North Bristol NHS Trust, February 2019 on behalf of the GMS Renal Specialist Test Group. Gene Symbol submitted: CD2AP; Suggested initial gene rating: amber; Evidence for inclusion: PMID: 30612599; PMID: 17713465 ; Other comments: Presumed recessive. Reported in multiple unrelated patients, however some of these reported variants now have high MAF. More convincing in two unrelated families: [Full text of PMID:30612599 unavailable, published Jan 2019 - reported hom variant in three affected sibs, not in gnomAD; PMID: 17713465: hom variant in one patient, not in gnomAD]. Reported 3x het VUS in SRNS cohort >600 patients.

Created: 4 Feb 2019, 10:41 a.m.

Mode of inheritance
Unknown

Phenotypes
Glomerulosclerosis, focal segmental, 3 #607832

Publications

• 30612599
• 17713465
• 10514378
• 12764198

Variants in this GENE are reported as part of current diagnostic practice

Comment on list classification: Only 1 family.

Created: 16 May 2016, 8:19 p.m.

I don't know

Currently on UK diagnostic panel, 2 VUS cases in lab over 300 tested. Listed in several reviews. Reported in literature but pathogenicity not clearly evidenced.

Created: 19 Oct 2015, 2:10 p.m.

Mode of inheritance
Unknown

Publications

• Kidney International (2007) 72, 1198–1203

Variants in this GENE are reported as part of current diagnostic practice