Is EOMES p.Ser222Arg (c.666C>A) pathogenic?

EOMES p.Ser222Arg (c.666C>A) is classified Uncertain significance in EOMES (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-25). AlphaMissense: ambiguous (0.4199); Very rare (popmax 0.00119%, sas).

How common is EOMES p.Ser222Arg (c.666C>A) in the general population?

EOMES p.Ser222Arg (c.666C>A) is very rare (popmax 0.00119%, sas) (gnomAD).

What do computational predictors say about EOMES p.Ser222Arg (c.666C>A)?

AlphaMissense predicts ambiguous (score 0.4199) — an in-silico prediction, not a clinical call.

EOMES p.Ser222Arg

c.666C>A · rs1475618857 · VCV2291165

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4199 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4199	ambiguous
REVEL	0.13	moderately benign-leaning
SaProt	LLR -9.50	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -1.2, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 779 bp · p 0.00084 · regional, not allelic
Overall
CADD	16.56	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00119% South Asian · 1/84,180 alleles

Overall 6.48e-05% 1/1,542,496 alleles · very rare exomes 1/1,390,340 · genomes 0/152,156 · 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.Ser222Arg
Coding: c.666C>A
MANE Select: NM_001278182
dbSNP: rs1475618857
Type: single nucleotide variant
Location: chr3:27721629 (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.Ser222Asn 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-ser222arg (accessed [today's date]).

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