Is EPS15 p.Arg249Cys (c.745C>T) pathogenic?

EPS15 p.Arg249Cys (c.745C>T) is classified Uncertain significance in EPS15 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: ambiguous (0.378); Very rare (popmax 0.00333%, amr).

How common is EPS15 p.Arg249Cys (c.745C>T) in the general population?

EPS15 p.Arg249Cys (c.745C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about EPS15 p.Arg249Cys (c.745C>T)?

AlphaMissense predicts ambiguous (score 0.378) — an in-silico prediction, not a clinical call.

EPS15 p.Arg249Cys

c.745C>T · rs754767920 · VCV2492793

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.378 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Computational evidence

Protein change
AlphaMissense	0.378	ambiguous
REVEL	0.328	indeterminate
SaProt	LLR -12.05	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.72 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 163 kb · p 0.94 · regional, not allelic
Overall
CADD	33.0	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 0.00333% Admixed American · 2/59,972 alleles

Filtering AF 0.000954% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00143% 23/1,612,914 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,986
South Asian	0.0022%	45,524
Remaining individualsnot grpmax-eligible	0.0016%	62,436
European (non-Finnish)	0.00153%	65,512

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: EPS15
Protein: p.Arg249Cys
Coding: c.745C>T
MANE Select: NM_001981
dbSNP: rs754767920
Type: single nucleotide variant
Location: chr1:51447012 (GRCh38)
Gene constraint: LOEUF 0.849 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.60 · 13 PDB
Residue 249: the 'interaction with dab2' region; the ef-hand 3 domain; the eh 3 domain; an α-helix

Full EPS15 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPS15 p.Ala208Ser Uncertain significance ★ ⚠ same type
EPS15 p.Ala2Ser Uncertain significance ★ ⚠ same type
EPS15 p.Ala39Thr Uncertain significance ★ ⚠ same type
EPS15 p.Ala423Val Uncertain significance ★ ⚠ same type
EPS15 p.Ala4Thr Uncertain significance ★ ⚠ same type
EPS15 p.Ala560Ser Uncertain significance ★ ⚠ same type
EPS15 p.Ala613Gly Uncertain significance ★ ⚠ same type
EPS15 p.Ala667Thr Uncertain significance ★ ⚠ 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/eps15-p-arg249cys (accessed [today's date]).

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