FYB2

Chr 1

FYN binding protein 2

Also known as: ARAP, C1orf168

NCBI Gene: 199920 ENSG00000187889 UniProt: Q5VWT5 OMIM: 618478

This protein functions as an adapter in T-cell receptor signaling and integrin-mediated T-cell adhesion, playing a critical role in T-cell activation. Mutations cause autosomal recessive combined immunodeficiency with autoimmunity and allergies, typically presenting in early childhood with recurrent infections and immune dysregulation. The gene shows low constraint to loss-of-function variants, consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

Involved in T cell receptor signaling pathway and cell adhesion mediated by integrin. Located in immunological synapse and membrane raft. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.70

Clinical Summary— FYB2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

6 VUS of 33 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.70LOEUF

pLI 0.000

Z-score -2.09

OE 1.36 (1.09–1.70)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.33Z-score

OE missense 1.05 (0.96–1.14)

379 obs / 361.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.36 (1.09–1.70)

0≤0.351.4

Missense OE?1.05 (0.96–1.14)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 54 / 39.8Missense obs/exp: 379 / 361.4Syn Z: 0.19

This gene — mechanism propensity

0.74top 25%

GOF

0.7028th %ile

LOF

0.3357th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

33 submitted variants in ClinVar

ClinVar

Classification Summary

VUS6

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	6	0	6
Likely Benign	0	1	1
Benign	0	0	0
Total	6	1	7

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

9 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap FYB2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →