Is EYS p.Asp646Ala (c.1937A>C) pathogenic?

EYS p.Asp646Ala (c.1937A>C) is classified Uncertain significance in EYS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-10). AlphaMissense: likely benign (0.1708); Ultra-rare (popmax 0.0122%, eas); Associated with Inborn genetic diseases.

What condition is associated with EYS p.Asp646Ala (c.1937A>C)?

EYS p.Asp646Ala (c.1937A>C) is associated with Inborn genetic diseases (ClinVar).

How common is EYS p.Asp646Ala (c.1937A>C) in the general population?

EYS p.Asp646Ala (c.1937A>C) is ultra-rare (popmax 0.0122%, eas) (gnomAD).

What do computational predictors say about EYS p.Asp646Ala (c.1937A>C)?

AlphaMissense predicts likely benign (score 0.1708) — an in-silico prediction, not a clinical call.

EYS p.Asp646Ala

c.1937A>C · rs780527503 · VCV2201498

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1708 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1708	likely benign
REVEL	0.177	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 0.28	GERP -1.2
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	14.28	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 0.0122% East Asian · 5/40,900 alleles

Filtering AF 0.00479% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000709% 11/1,551,136 alleles · ultra-rare exomes 9/1,399,018 · genomes 2/152,118 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0122%	8,180
South Asian	0.00476%	21,013
African / African-American	0.00137%	73,120
European (non-Finnish)	8.72e-05%	1,146,470

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.Asp646Ala
Coding: c.1937A>C
MANE Select: NM_001142800
dbSNP: rs780527503
Type: single nucleotide variant
Location: chr6:65295949 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)
Residue 646: the egf-like 7 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EYS p.Asp646Gly Uncertain significance ★ ⚠ same residue
EYS p.Ala1174Glu Uncertain significance ★★ same condition
EYS p.Ala1465Thr Uncertain significance ★★ ⚠ same condition
EYS p.Ala1520Asp Uncertain significance ★★ ⚠ same condition
EYS p.Ala1520Gly Uncertain significance ★★ ⚠ same condition
EYS p.Ala1984Thr Uncertain significance ★★ same condition
EYS p.Ala2728Val Uncertain significance ★★ ⚠ same condition
EYS p.Ala2729Val 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/eys-p-asp646ala (accessed [today's date]).

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