Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: CD48

Green List (high evidence)

Comment on list classification: There are two unrelated patients with two different variants affecting the same residue and functional evidence available in support of the association of CD48 gene with immune dysregulation. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 31 Jul 2026, 11:22 a.m. | Last Modified: 31 Jul 2026, 11:22 a.m.

Panel Version: 9.54

PMID:31419545 (2019) reported a 24-year-old patient with recurrent hyperinflammatory flares resembling macrophage activation syndrome/secondary HLH, with cytopenias, markedly raised ferritin, IL‑6, sCD25 and IL‑18, and elevated activated (HLA‑DR⁺) T cells. Whole‑exome sequencing identified a heterozygous missense variant in CD48 gene (c.659C>A, p.Ser220Tyr). Functionally, the variant causes reduced CD48 cell‑surface expression, altered NK‑cell subsets and cytokine responses, impaired cytotoxicity, and abnormal 2B4‑mediated signaling, supporting CD48 haploinsufficiency as a driver of the patient’s hyperinflammatory phenotype.

PMID:41984595 (2026) reported a second, unrelated 22-year old patient with similar features of immune dysregulation and a missense variant affecting the same residue (c.659C>T, p.Ser220Phe). Functional evidence showed that CD48 variants lead to reduced CD48 surface expression with intracellular retention and ER‑stress activation, causing T‑cell apoptosis, restricted/oligoclonal TCR repertoires, impaired antiviral responses, and exaggerated inflammation in patients. CD48‑deficient, virally infected mice mirror these defects with delayed antiviral immunity, poor viral clearance, and pronounced inflammation, confirming that loss of proper CD48 localisation directly compromises T‑cell survival and function and predisposes to hyperinflammation.

This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen (last accessed 31 July 2026).

Created: 31 Jul 2026, 11:19 a.m. | Last Modified: 31 Jul 2026, 11:19 a.m.

Panel Version: 9.50

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
inborn error of immunity, MONDO:0003778

Publications

• 31419545
• 41984595

Red List (low evidence)

Volkmer et al. described a patient with heterozygous p.S220Y causing HLH-like phenotype.
Variant is likely dominant negative
Further patient described recently validating DN mechanism:
https://rupress.org/jhi/article/2/CIS2026/eCIS2026abstract.95/281844/S220-Variants-of-Human-CD48-Result-in-Aberrant
Sources: Literature

Created: 1 May 2026, 7:51 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Hemophagocytic lymphohistiocytosis; Urticaria; Hives; Inflammation; Fever; Hepatosplenomegaly

Publications

• 31419545

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments