Is FES p.Gly641Ala (c.1922G>C) pathogenic?

FES p.Gly641Ala (c.1922G>C) is classified Uncertain significance in FES (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-01). AlphaMissense: likely pathogenic (0.7642); Ultra-rare (popmax 0.0168%, mid).

How common is FES p.Gly641Ala (c.1922G>C) in the general population?

FES p.Gly641Ala (c.1922G>C) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

What do computational predictors say about FES p.Gly641Ala (c.1922G>C)?

AlphaMissense predicts likely pathogenic (score 0.7642) — an in-silico prediction, not a clinical call.

FES p.Gly641Ala

c.1922G>C · rs149647375 · VCV2468716

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7642 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7642	likely pathogenic
REVEL	0.527	indeterminate
SaProt	LLR -10.77	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 9.3e-05 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0168% Middle Eastern · 1/5,960 alleles

Filtering AF 0.000618% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000476%

Overall 0.000999% 16/1,601,482 alleles · ultra-rare exomes 14/1,449,248 · genomes 2/152,234 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,960
Remaining individualsnot grpmax-eligible	0.00161%	61,938
African / African-American	0.00134%	74,810
European (non-Finnish)	0.00111%	90,258

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: FES
Protein: p.Gly641Ala
Coding: c.1922G>C
MANE Select: NM_002005
dbSNP: rs149647375
Type: single nucleotide variant
Location: chr15:90893291 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.63 · 12 PDB
Residue 641: the protein kinase domain

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

Similar variants

FES p.Ala588= Benign ★★ same type
FES p.Leu459= Benign ★★ same type
FES p.Met323Val Benign ★★ same type
FES p.Ala192Pro Uncertain significance ★ ⚠ same type
FES p.Ala22Asp Uncertain significance ★ ⚠ same type
FES p.Ala243Val Uncertain significance ★ ⚠ same type
FES p.Ala370Val Uncertain significance ★ ⚠ same type
FES p.Ala45Pro 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/fes-p-gly641ala (accessed [today's date]).

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