Is GRB2 p.Ala82Ser (c.244G>T) pathogenic?

GRB2 p.Ala82Ser (c.244G>T) is classified Uncertain significance in GRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-17). AlphaMissense: likely benign (0.2059); Absent from gnomAD v4.1.

How common is GRB2 p.Ala82Ser (c.244G>T) in the general population?

GRB2 p.Ala82Ser (c.244G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GRB2 p.Ala82Ser (c.244G>T)?

AlphaMissense predicts likely benign (score 0.2059) — an in-silico prediction, not a clinical call.

GRB2 p.Ala82Ser

c.244G>T · VCV3855613

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2059 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2059	likely benign
REVEL	0.369	indeterminate
SaProt	LLR -6.52	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.76, phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 68 kb · p 4.4e-10 · regional, not allelic
Overall
CADD	24.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GRB2
Protein: p.Ala82Ser
Coding: c.244G>T
MANE Select: NM_002086
Type: single nucleotide variant
Location: chr17:75325953 (GRCh38)
Gene constraint: LOEUF 0.216 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 88.89 · 58 PDB
Residue 82: the sh2 domain; a β-strand

Full GRB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GRB2 p.His79= Benign ★★ same type
GRB2 p.Arg207Cys Uncertain significance ★ same type
GRB2 p.Arg215Trp Uncertain significance ★ ⚠ same type
GRB2 p.Asn126Ser Uncertain significance ★ ⚠ same type
GRB2 p.Asp133Asn Uncertain significance ★ ⚠ same type
GRB2 p.Asp23Asn Uncertain significance ★ same type
GRB2 p.Glu87Asp 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/grb2-p-ala82ser (accessed [today's date]).

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