Is EYS p.Val112Ala (c.335T>C) pathogenic?

EYS p.Val112Ala (c.335T>C) is classified Uncertain significance in EYS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-31). AlphaMissense: likely benign (0.1211); Ultra-rare (popmax 0.016%, afr).

How common is EYS p.Val112Ala (c.335T>C) in the general population?

EYS p.Val112Ala (c.335T>C) is ultra-rare (popmax 0.016%, afr) (gnomAD).

What do computational predictors say about EYS p.Val112Ala (c.335T>C)?

AlphaMissense predicts likely benign (score 0.1211) — an in-silico prediction, not a clinical call.

EYS p.Val112Ala

c.335T>C · rs562862906 · VCV2084089

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1211 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1211	likely benign
REVEL	0.116	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.18	GERP -0.93
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	17.15	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.016% African / African-American · 12/75,054 alleles

Filtering AF 0.0092% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0072%

Overall 0.00136% 22/1,614,194 alleles · ultra-rare exomes 15/1,461,868 · genomes 7/152,326 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,254
Remaining individualsnot grpmax-eligible	0.008%	12,502
East Asian	0.00446%	22,441
South Asian	0.0022%	45,541
European (non-Finnish)	8.47e-05%	1,180,034

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: EYS
Protein: p.Val112Ala
Coding: c.335T>C
MANE Select: NM_001142800
dbSNP: rs562862906
Type: single nucleotide variant
Location: chr6:65495076 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)
Residue 112: a UniProt-annotated variant site (in)

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

Similar variants

EYS p.Val112Ile Benign/Likely benign ★★ same residue
EYS p.Val112Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
EYS c.1056+1G>A Pathogenic/Likely pathogenic ★★ same type
EYS c.1056+3A>C Likely pathogenic ★★ same type
EYS c.1057-1G>A Likely pathogenic ★★ same type
EYS c.1184+1G>A Pathogenic/Likely pathogenic ★★ same type
EYS c.1184+1G>T Likely pathogenic ★★ same type
EYS c.1185-1G>A Likely pathogenic ★★ 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/eys-p-val112ala (accessed [today's date]).

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