GRAP

Chr 17AR

GRB2 related adaptor protein

Also known as: DFNB114

NCBI Gene: 10750ENSG00000154016UniProt: Q13588

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]

Primary Disease Associations & Inheritance

Deafness, autosomal recessive 114MIM #618456
AR
133
ClinVar variants
99
Pathogenic / LP
0.11
pLI score
0
Active trials
Clinical Summary— GRAP
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Gene-Disease Validity (ClinGen)
nonsyndromic genetic hearing loss · ARLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.11) — loss-of-function variants are relatively tolerated in the population.
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ClinVar Variants
99 Pathogenic / Likely Pathogenic· 26 VUS of 133 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.14Z-score
OE missense 0.64 (0.50–0.81)
49 obs / 77.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.39 (0.16–1.22)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.64 (0.50–0.81)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.89
0≤1.21.6
LoF obs/exp: 2 / 5.1Missense obs/exp: 49 / 77.1Syn Z: 0.50

ClinVar Variant Classifications

133 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic97
Likely Pathogenic2
VUS26
Likely Benign5
Benign3
97
Pathogenic
2
Likely Pathogenic
26
VUS
5
Likely Benign
3
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
97
0
97
Likely Pathogenic
0
1
1
0
2
VUS
0
15
11
0
26
Likely Benign
0
2
1
2
5
Benign
0
0
3
0
3
Total0181132133

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

View in ClinVar →

Protein Context — Lollipop Plot

GRAP · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Deafness, autosomal recessive 114

MIM #618456

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Dysfunction of GRAP, encoding the GRB2-related adaptor protein, is linked to sensorineural hearing loss.
Li C et al.·Proc Natl Acad Sci U S A
2019
miR-654-5p Targets GRAP to Promote Proliferation, Metastasis, and Chemoresistance of Oral Squamous Cell Carcinoma Through Ras/MAPK Signaling.
Lu M et al.·DNA Cell Biol
2018
Identification of tumor associated neutrophils-related genes in triple-negative breast cancer for predicting prognosis and therapeutic response through integrated single-cell analysis.
Li K et al.·Front Immunol
2025
Identification of tumor antigens and immune subtypes of glioma for mRNA vaccine development.
Chen Z et al.·Cancer Med
2022
Quantitative mass spectrometry of diabetic kidney tubules identifies GRAP as a novel regulator of TGF-beta signaling.
Cummins TD et al.·Biochim Biophys Acta
2010
Prognosis prediction model based on competing endogenous RNAs for recurrence of colon adenocarcinoma.
Jin LP et al.·BMC Cancer
2020Functional
Routine use of antibiotic prophylaxis in low-risk laparoscopic cholecystectomy is unnecessary: a randomized clinical trial.
Shah JN et al.·Asian J Surg
2012
Solitary fibrous tumor of the central nervous system: a clinicopathologic study of 24 cases.
Chen H et al.·Acta Neurochir (Wien)
2012Cohort
Clinical trials of antiarrhythmic therapy--an improper answer to a proper question?
Lubsen J·Cardiology
1987Clinical trial
An attentional grasp reflex in patients with Alzheimer's disease.
Maruff P et al.·Neuropsychologia
1995Clinical trial
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools