Is EOMES p.Val491Ile (c.1471G>A) pathogenic?

EOMES p.Val491Ile (c.1471G>A) is classified Uncertain significance in EOMES (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: likely benign (0.0786); Ultra-rare (popmax 0.0117%, amr).

How common is EOMES p.Val491Ile (c.1471G>A) in the general population?

EOMES p.Val491Ile (c.1471G>A) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about EOMES p.Val491Ile (c.1471G>A)?

AlphaMissense predicts likely benign (score 0.0786) — an in-silico prediction, not a clinical call.

EOMES p.Val491Ile

c.1471G>A · VCV4664549

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0786 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0786	likely benign
REVEL	0.242	benign-leaning
SaProt	LLR -7.09	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 4.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 685 bp · p 0.17 · regional, not allelic
Overall
CADD	27.0	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V472I vs ClinVar V491I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/59,966 alleles

Filtering AF 0.00544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00446% 72/1,613,702 alleles · ultra-rare exomes 64/1,461,844 · genomes 8/151,858 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,567
African / African-American	0.00535%	18,696
Remaining individualsnot grpmax-eligible	0.0048%	20,826
European (non-Finnish)	0.00458%	21,851
South Asian	0.00329%	30,355
East Asian	0.00223%	44,880

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: EOMES
Protein: p.Val491Ile
Coding: c.1471G>A
MANE Select: NM_001278182
Type: single nucleotide variant
Location: chr3:27717717 (GRCh38)
Gene constraint: LOEUF 0.493 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 56.74

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

Similar variants

EOMES p.Tyr231Cys Uncertain significance ★★ ⚠ same type
EOMES p.Glu113= Likely benign ★★ same type
EOMES p.Pro641= Benign ★★ same type
EOMES p.Ser392= Likely benign ★★ same type
EOMES p.Ser91Arg Likely benign ★★ same type
EOMES p.Ala118Pro Uncertain significance ★ ⚠ same type
EOMES p.Ala17Pro Uncertain significance ★ ⚠ same type
EOMES p.Ala206Gly 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/eomes-p-val491ile (accessed [today's date]).

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