Is EOMES p.Pro616Ala (c.1846C>G) pathogenic?

EOMES p.Pro616Ala (c.1846C>G) is classified Uncertain significance in EOMES (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely benign (0.0857); Ultra-rare (popmax 0.0167%, amr).

How common is EOMES p.Pro616Ala (c.1846C>G) in the general population?

EOMES p.Pro616Ala (c.1846C>G) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about EOMES p.Pro616Ala (c.1846C>G)?

AlphaMissense predicts likely benign (score 0.0857) — an in-silico prediction, not a clinical call.

EOMES p.Pro616Ala

c.1846C>G · VCV4249439

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0857 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0857	likely benign
REVEL	0.665	pathogenic-leaning
SaProt	LLR -6.96	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 0.93, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 685 bp · p 0.17 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P597A vs ClinVar P616A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Admixed American · 10/60,000 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.0013% 21/1,613,988 alleles · ultra-rare exomes 19/1,461,872 · genomes 2/152,116 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	6,000
East Asian	0.00223%	44,880
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000763%	131,113

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.Pro616Ala
Coding: c.1846C>G
MANE Select: NM_001278182
Type: single nucleotide variant
Location: chr3:27717342 (GRCh38)
Gene constraint: LOEUF 0.493 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 56.74
Residue 597 UniProt numbering: the 'required for transcription activation' region

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-pro616ala (accessed [today's date]).

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