Is EYS p.Asp646Gly (c.1937A>G) pathogenic?

EYS p.Asp646Gly (c.1937A>G) is classified Uncertain significance in EYS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-18). AlphaMissense: likely benign (0.1427); Ultra-rare (popmax 0.0167%, mid).

How common is EYS p.Asp646Gly (c.1937A>G) in the general population?

EYS p.Asp646Gly (c.1937A>G) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about EYS p.Asp646Gly (c.1937A>G)?

AlphaMissense predicts likely benign (score 0.1427) — an in-silico prediction, not a clinical call.

EYS p.Asp646Gly

c.1937A>G · rs780527503 · VCV2912115

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1427 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1427	likely benign
REVEL	0.248	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	14.56	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 0.0167% Middle Eastern · 1/5,994 alleles

Overall 0.000193% 3/1,551,136 alleles · ultra-rare exomes 3/1,399,018 · genomes 0/152,118 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,994
Remaining individualsnot grpmax-eligible	0.00166%	60,146
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.Asp646Gly
Coding: c.1937A>G
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

Similar variants

EYS p.Asp646Ala Uncertain significance ★★ ⚠ 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
EYS c.1299+1G>T Pathogenic/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-asp646gly (accessed [today's date]).

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