Is EOMES p.Pro21Ser (c.61C>T) pathogenic?

EOMES p.Pro21Ser (c.61C>T) is classified Uncertain significance in EOMES (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-13). AlphaMissense: likely benign (0.0612); Very rare (popmax 0.00672%, afr).

How common is EOMES p.Pro21Ser (c.61C>T) in the general population?

EOMES p.Pro21Ser (c.61C>T) is very rare (popmax 0.00672%, afr) (gnomAD).

What do computational predictors say about EOMES p.Pro21Ser (c.61C>T)?

AlphaMissense predicts likely benign (score 0.0612) — an in-silico prediction, not a clinical call.

EOMES p.Pro21Ser

c.61C>T · VCV3845132

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0612 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00672%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0612	likely benign
REVEL	0.225	benign-leaning
SaProt	LLR -5.69	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP -0.31, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 779 bp · p 0.00084 · regional, not allelic
Overall
CADD	19.1	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

Grpmax group 0.00672% African / African-American · 5/74,362 alleles

Filtering AF 0.00256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00163%

Overall 0.000311% 5/1,605,258 alleles · very rare exomes 2/1,453,068 · genomes 3/152,190 · joint denominator

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.Pro21Ser
Coding: c.61C>T
MANE Select: NM_001278182
Type: single nucleotide variant
Location: chr3:27722234 (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.Pro21Arg Uncertain significance ★ ⚠ same residue
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

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-pro21ser (accessed [today's date]).

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