Is GRB7 p.Val164Met (c.490G>A) pathogenic?

GRB7 p.Val164Met (c.490G>A) is classified Uncertain significance in GRB7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-13). AlphaMissense: ambiguous (0.4227); Ultra-rare (popmax 0.0121%, sas).

How common is GRB7 p.Val164Met (c.490G>A) in the general population?

GRB7 p.Val164Met (c.490G>A) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about GRB7 p.Val164Met (c.490G>A)?

AlphaMissense predicts ambiguous (score 0.4227) — an in-silico prediction, not a clinical call.

GRB7 p.Val164Met

c.490G>A · VCV4032143

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4227 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Computational evidence

Protein change
AlphaMissense	0.4227	ambiguous
REVEL	0.291	indeterminate
SaProt	LLR -10.06	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP -1, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 3,977 bp · p 5e-06 · regional, not allelic
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0121% South Asian · 11/91,086 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.00161% 26/1,614,164 alleles · ultra-rare exomes 23/1,461,836 · genomes 3/152,328 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,281
Admixed American	0.01%	10,005
Remaining individualsnot grpmax-eligible	0.0048%	20,835
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
European (non-Finnish)	0.000424%	236,006

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GRB7
Protein: p.Val164Met
Coding: c.490G>A
MANE Select: NM_005310
Type: single nucleotide variant
Location: chr17:39743206 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.04 · 14 PDB
Residue 164: the ras-associating domain; an α-helix

Full GRB7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GRB7 c.1210-4A>G Benign ★★ same type
GRB7 c.307-4G>A Benign ★★ same type
GRB7 p.Pro362Leu Benign ★★ same type
GRB7 p.Thr419Lys Benign ★★ same type
GRB7 c.-17T>C Uncertain significance ★ same type
GRB7 c.-2C>A Uncertain significance ★ same type
GRB7 c.-45G>A Uncertain significance ★ same type
GRB7 c.-50G>A Uncertain significance ★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/grb7-p-val164met (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown