Monogenic diabetes

Gene: APPL1

I don't know

Comment on list classification: There are 4 pedigrees reported in literature with monoallelic APPL1 variants and a diagnosis of familial MODY (PMID: 26073777; 38464380). The variants have good evidence of impaired expression and/or function. However, the gene-disease association has recently been Refuted in ClinGen. Based on incomplete penetrance and the lack of enrichment for APPL1 variants in a large MODY cohort (PMID: 40779032), this gene will be suggested for a downgrade to Amber on Monogenic diabetes. Expert review will be sought regarding inclusion, as detection of extremely rare / low-penetrance MODY-causing variants in APPL1 may still be pertinent.

Created: 26 Feb 2026, 3:35 p.m. | Last Modified: 26 Feb 2026, 3:36 p.m.

Panel Version: 3.8

EVIDENCE AGAINST ASSOCIATION:
PMID: 40779032 Sriram et al., 2025
Cohort of 2,571 unrelated individuals of European ancestry with clinically suspected MODY. Genes assessed: APPL1 NM_012096.3, HNF1A NM_000545.8, NEUROD1 NM_002500.5, PDX1 NM_000209.4, RFX6 NM_173560.4, and WFS1 NM_006005.3.
Frequency and co-segregation analysis examined specific, previously published variants and did not assess if other rare variants in these genes cause MODY.
Conflicting evidence:
- 8/23 individuals originally reported in PMID: 26073777 did not have diabetes, despite carrying the variant and being over age 25 (potentially reduced penetrance/have not yet developed the disease)
- Authors claim LOF variants seem generally common in gnomAD - too common to cause MODY (however, pLI score for APPL1 is 0.88 - likely to be a dosage sensitive gene)
- MODY cohort showed no enrichment for protein-truncating variants or damaging missense variants in APPL1. Other genes (NEUROD1 and PDX1) showed enrichment in the MODY cohort.

PMID: 32854233 Ivanoshchuk et al., 2020
Cohort of 151 Russian patients with early-onset MODY/Type 2 diabetes diagnosis, sequenced using WES or targeted sequencing. APPL1 polymorphism rs11544593 was flagged as a risk factor, but no pathogenic APPL1 variants detected.

The gene was reclassified from Moderate to Refuted by ClinGen in Feb 2026 (Monogenic diabetes panel), on the basis of evidence presented in PMID: 40779032.

EVIDENCE SUPPORTING ASSOCIATION:
PMID: 38464380 Shi et al., 2024
A total of five novel APPL1 mutations were identified in patients with diabetes (onset at ages 8, 12, 13, 21, and 39 years), including four missense mutations (Asp632Tyr, Arg633His, Arg532Gln, and Ile642Met) and one intronic mutation (1153-16A>T). Seq method: WES.
Of these 5, 2 variants were classed as pathogenic after analysis: APPL1 c.1894G>T (p.Asp632Tyr) and c.1595G>A (p.Arg532Gln). These variants have 2 and 13 heterozygotes reported in gnomAD v4.1.0, respectively. Incomplete pentrance noted - P3 and his grandfather had diabetes, but his father did not (also het for APPL1 p.Arg532Gln). Patient 1 had an affected father and grandmother, but genotyping was not done. Patients 2, 4, and 5 were concluded to carry non-pathogenic APPL1 variants, and were diagnosed with type 2 diabetes instead.

Functional assessment: HEK293 cells transfected with mutated plasmids; the mRNA expression level of APPL1 Asp632Tyr variant decreased by 98% (P = 0.001) compared with WT-APPL1, resulting in no protein expression; mRNA expression of Arg532Gln variant decreased by 14%; protein expression of the p.Arg532Gln variant was significantly reduced compared with WT APPL1.

PMID: 26073777 Prudente et al., 2015
Report of 2 large families with high prevalence of diabetes. Variants identified: c.1655T>A, p.Leu552* (not in gnomAD v4.1.0) and c.280G>A, p.Asp94Asn (5 heterozygous individuals reported in gnomAD v4.1.0). Seq method: WES.
F1: Italian family, APPL1 c.1655T>A, p.Leu552* detected; individuals diagnosed with diabetes aged 20-50.
F2: US family, APPl1 c.280G>A, p.Asp94Asn detected; individuals diagnosed with diabetes aged 10-48.
Lack of mutations in the six most common MODY genes (HNF4A, GCK, HNF1A, PDX1, HNF1B, and NEUROD1) was a prerequisite for this study and confirmed in the two families.

Functional evidence: the p.Leu552∗ alteration abolishes APPL1 protein expression in HepG2 transfected cells; p.Asp94Asn alteration causes significant reduction in the enhancement of the insulin-stimulated AKT2 and GSK3β phosphorylation that is observed after wild-type APPL1 transfection. APPL1 has a key regulatory role in glucose metabolism.

Created: 26 Feb 2026, 3:25 p.m. | Last Modified: 26 Feb 2026, 3:44 p.m.

Panel Version: 3.8

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
{Maturity-onset diabetes of the young, type 14}, OMIM:616511

Publications

• 26073777
• 32854233
• 38464380
• 40779032

Green List (high evidence)

Comment on list classification: Promoted from red to green as advised via email communication with Jane Houghton (South West GLH).

Created: 28 Jan 2019, 9:37 a.m.

Initial gene list and info collated by Sian Ellard, University of Exeter Medical School, August 2018 on behalf of the GMS Endocrinology specialist test group. Gene Symbol submitted: APPL1; Suggested intial gene rating: Green; Evidence for inclusion: none given; Evidence for exclusion: none given; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none given; Phenotypes: Diabetes.

Created: 11 Jan 2019, 10:04 a.m.