Is GRB7 p.Ser197Phe (c.590C>T) pathogenic?

GRB7 p.Ser197Phe (c.590C>T) is classified Uncertain significance in GRB7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-11). AlphaMissense: likely benign (0.1136); Absent from gnomAD v4.1.

How common is GRB7 p.Ser197Phe (c.590C>T) in the general population?

GRB7 p.Ser197Phe (c.590C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GRB7 p.Ser197Phe (c.590C>T)?

AlphaMissense predicts likely benign (score 0.1136) — an in-silico prediction, not a clinical call.

GRB7 p.Ser197Phe

c.590C>T · VCV3855624

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1136 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1136	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -9.06	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4	GERP 1.4, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 3,977 bp · p 5e-06 · regional, not allelic
Overall
CADD	23.6	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: GRB7
Protein: p.Ser197Phe
Coding: c.590C>T
MANE Select: NM_005310
Type: single nucleotide variant
Location: chr17:39743397 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.04 · 14 PDB

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-ser197phe (accessed [today's date]).

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