Is EYA4 p.Ser331Arg (c.991A>C) pathogenic?

EYA4 p.Ser331Arg (c.991A>C) is classified Uncertain significance in EYA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-12). AlphaMissense: likely pathogenic (0.6943); Very rare (popmax 0.0022%, sas); Associated with Cardiovascular phenotype.

What condition is associated with EYA4 p.Ser331Arg (c.991A>C)?

EYA4 p.Ser331Arg (c.991A>C) is associated with Cardiovascular phenotype (ClinVar).

How common is EYA4 p.Ser331Arg (c.991A>C) in the general population?

EYA4 p.Ser331Arg (c.991A>C) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about EYA4 p.Ser331Arg (c.991A>C)?

AlphaMissense predicts likely pathogenic (score 0.6943) — an in-silico prediction, not a clinical call.

EYA4 p.Ser331Arg

c.991A>C · rs2534855734 · VCV2625465

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6943 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.6943	likely pathogenic
REVEL	0.6	indeterminate
SaProt	LLR -6.10	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 254 kb · p 0.0025 · regional, not allelic
Overall
CADD	26.9	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 0.0022% South Asian · 2/91,074 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000124% 2/1,613,932 alleles · very rare exomes 2/1,461,668 · genomes 0/152,264 · 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: EYA4
Protein: p.Ser331Arg
Coding: c.991A>C
MANE Select: NM_004100
dbSNP: rs2534855734
Type: single nucleotide variant
Location: chr6:133481483 (GRCh38)
Gene constraint: LOEUF 0.536 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.79
Residue 331: a UniProt-annotated variant site (in dfna10); the 'disordered' region

Full EYA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EYA4 c.1739-1G>A Likely pathogenic ★★ same condition
EYA4 c.-2A>G Uncertain significance ★★ same condition
EYA4 p.Ala253Thr Uncertain significance ★★ ⚠ same condition
EYA4 p.Ala287Val Uncertain significance ★★ ⚠ same condition
EYA4 p.Ala292Thr Uncertain significance ★★ ⚠ same condition
EYA4 p.Ala402Ser Uncertain significance ★★ ⚠ same condition
EYA4 p.Ala516Thr Uncertain significance ★★ ⚠ same condition
EYA4 p.Ala79Thr Uncertain significance ★★ ⚠ same condition

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/eya4-p-ser331arg (accessed [today's date]).

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