Is EYS p.Ser746Phe (c.2237C>T) pathogenic?

EYS p.Ser746Phe (c.2237C>T) is classified Uncertain significance in EYS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-08). AlphaMissense: ambiguous (0.5226); Ultra-rare (popmax 0.0167%, mid); Associated with Inborn genetic diseases.

What condition is associated with EYS p.Ser746Phe (c.2237C>T)?

EYS p.Ser746Phe (c.2237C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EYS p.Ser746Phe (c.2237C>T) in the general population?

EYS p.Ser746Phe (c.2237C>T) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about EYS p.Ser746Phe (c.2237C>T)?

AlphaMissense predicts ambiguous (score 0.5226) — an in-silico prediction, not a clinical call.

EYS p.Ser746Phe

c.2237C>T · VCV4618988

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5226 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5226	ambiguous
REVEL	0.713	pathogenic-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	Δ0.20	donor gain · deltas
Constraint at this position
Conservation	phyloP 3	GERP 0.16, phastCons 0.32
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

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 · 1/5,988 alleles

Filtering AF 0.0073% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00561%

Overall 0.000774% 12/1,551,212 alleles · ultra-rare exomes 12/1,398,942 · genomes 0/152,270 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,988
South Asian	0.0131%	7,639

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.Ser746Phe
Coding: c.2237C>T
MANE Select: NM_001142800
Type: single nucleotide variant
Location: chr6:64997604 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)
Residue 746: the egf-like 9; calcium-binding 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.Ser746Thr 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-ser746phe (accessed [today's date]).

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