Autoinflammatory disorders

Gene: FGR

Green List (high evidence)

Comment on list classification: There are two different autoinflammatory phenotypes reported with monoallelic FGR variants.
1. >10 unrelated cases with chronic recurrent multifocal osteomyelitis, of which two patients had missense variants, and functional evidence for these two variants and from mouse model available.
2. One large family with vasculitis and functional evidence available for the variant (although reduced penetrance as reported in the review below)

Based on this evidence, this gene can be promoted to green rating in the next GMS update.

Created: 31 Jul 2026, 10:48 a.m. | Last Modified: 31 Jul 2026, 10:48 a.m.

Panel Version: 9.50

PMID:31138708 (2019) reported whole-exome sequencing of 99 Chronic recurrent multifocal osteomyelitis (CRMO) patients including 88 trios and 11 dyads, of which 11 different rare exonic heterozygous variants in FGR gene were identified in 13 probands. These include two missense variants, p.Arg118Trp found in SH3 domain and and p.Pro525Ser variant found in C-terminal tail. Functional analysis showed p.Arg118Trp variant decreased kinase activity, while p.Pro525Ser showed increased kinase activity (gain-of-function). Studies on Ali18 mice carrying a gain‑of‑function missense mutation in the C‑terminal regulatory region of Fgr shiwed that it reduces its negative regulatory phosphorylation, and this aberrant Fgr activity is necessary and sufficient to drive the spontaneous sterile osteomyelitis and systemic low bone mineral density inflammatory phenotype.

PMID:41920357 (2026) reported three unrelated kindreds with sarcoma (Src) family of non-receptor tyrosine kinase (SFK)-associated vasculitis, of which one large family of 13 affected members across four generations was identified with a novel missense variant in FGR (p.Tyr523His). All clinically affected individuals (10) were heterozygous, while four unaffected members did not carry the variant. Two self-reported healthy members were also heterozygous, suggesting AD inheritance with incomplete penetrance or variable expressivity, although these two carriers have not undergone investigations for subclinical disease. Functional studies on p.Tyr523His variant showed ~50% reduced Fgr protein, enhanced STAT1/STAT5 signaling and increased CD11b/CD18 integrin expression.

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, 10:36 a.m. | Last Modified: 31 Jul 2026, 10:44 a.m.

Panel Version: 9.49

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
chronic recurrent multifocal osteomyelitis, MONDO:0009813; vasculitis, MONDO:0018882

Publications

• 31138708
• 41920357

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

Red List (low evidence)

Price-Kuehne et al. described very large kindred with autosomal dominant Gain of function due to loss of regulatory tyrosine in FGR
https://link.springer.com/article/10.1007/s10875-026-01998-z
Sources: Literature

Created: 14 Apr 2026, 7:09 p.m.

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

Phenotypes
Autoinflammatory disease; Cutaneous vasculitis; Lung inflammation; Lung fibrosis; Interstitial lung disease

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