Is GRB7 p.Ala90Val (c.269C>T) pathogenic?

GRB7 p.Ala90Val (c.269C>T) is classified Uncertain significance in GRB7 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-03). AlphaMissense: likely benign (0.0734); Ultra-rare (popmax 0.0237%, nfe).

How common is GRB7 p.Ala90Val (c.269C>T) in the general population?

GRB7 p.Ala90Val (c.269C>T) is ultra-rare (popmax 0.0237%, nfe) (gnomAD).

What do computational predictors say about GRB7 p.Ala90Val (c.269C>T)?

AlphaMissense predicts likely benign (score 0.0734) — an in-silico prediction, not a clinical call.

GRB7 p.Ala90Val

c.269C>T · rs200467116 · VCV2257303

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0734 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0237%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0734	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -7.36	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -1.1, phastCons 0.001
Regional constraint	o/e 1.18	unconstrained · MANE · 614 bp · p 0.035 · regional, not allelic
Overall
CADD	13.96	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0237% European (non-Finnish) · 277/1,168,898 alleles

Filtering AF 0.0214% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0205%

Overall 0.0176% 280/1,591,964 alleles · ultra-rare exomes 275/1,439,850 · genomes 5/152,114 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0237%	4,220
Remaining individualsnot grpmax-eligible	0.00489%	20,469

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.Ala90Val
Coding: c.269C>T
MANE Select: NM_005310
dbSNP: rs200467116
Type: single nucleotide variant
Location: chr17:39742679 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.04 · 14 PDB
Residue 90: the 'disordered' region

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-ala90val (accessed [today's date]).

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