GRAP

Chr 17AR

GRB2 related adaptor protein

Also known as: DFNB114

NCBI Gene: 10750 ENSG00000154016 UniProt: Q13588 OMIM: 604330

This gene encodes a cytoplasmic signaling protein that couples signals from receptor and cytoplasmic tyrosine kinases to the Ras signaling pathway through its SH2 and SH3 domains. Mutations cause autosomal recessive deafness-114, affecting inner ear function and hearing. The gene shows tolerance to loss-of-function variants (pLI = 0.11), consistent with the recessive inheritance pattern observed clinically.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the GRB2/Sem5/Drk family and functions as a cytoplasmic signaling protein which contains an SH2 domain flanked by two SH3 domains. The SH2 domain interacts with ligand-activated receptors for stem cell factor and erythropoietin, and facilitates the formation of a stable complex with the BCR-ABL oncoprotein. This protein also associates with the Ras guanine nucleotide exchange factor SOS1 (son of sevenless homolog 1) through its N-terminal SH3 domain. In general, it couples signals from receptor and cytoplasmic tyrosine kinases to the Ras signaling pathway. [provided by RefSeq, Jul 2012]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Deafness, autosomal recessive 114MIM #618456

Clinical highlights

Gene–disease validity (ClinGen)

Limited · nonsyndromic genetic hearing loss · AR · ClinGen 2026

not for standalone diagnostic reporting

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.22

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.22LOEUF

pLI 0.111

Z-score 1.28

OE 0.39 (0.16–1.22)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.14Z-score

OE missense 0.64 (0.50–0.81)

49 obs / 77.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.39 (0.16–1.22)

0≤0.351.4

Missense OE?0.64 (0.50–0.81)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 2 / 5.1Missense obs/exp: 49 / 77.1Syn Z: 0.50

Background carrier burden — how many people carry a rare variant somewhere in GRAP?

gnomAD v4 · ~730k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 310

218 rare PASS variants

Rare truncating (LoF)

1 in 7,500

25 rare PASS variants

Rare synonymous (reference)

1 in 730

62 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GRAP. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 480	1 in 13,000
South Asian	~43k	1 in 300	1 in 7,100
Remaining (unassigned)	~30k	1 in 210	none seen
European (Finnish)	~27k	1 in 2,600	≈ 1 in 8,100
Admixed American	~22k	1 in 170	none seen
African / African American	~21k	1 in 150	1 in 2,700
East Asian	~20k	1 in 170	none seen
Ashkenazi Jewish	~13k	1 in 1,400	≈ 1 in 5,500
Middle Eastern	~2,866	1 in 270	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 1 of 5 coding exons well covered in gnomAD exomes; exons 1, 2, 3 poorly covered; exon 5 marginal. Genomes: 2 of 5 (exons 1, 2, 3 below).? see exons ↓