Is EPS15 p.Asp61His (c.181G>C) pathogenic?

EPS15 p.Asp61His (c.181G>C) is classified Uncertain significance in EPS15 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-17). AlphaMissense: likely pathogenic (0.9528); Absent from gnomAD v4.1.

How common is EPS15 p.Asp61His (c.181G>C) in the general population?

EPS15 p.Asp61His (c.181G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EPS15 p.Asp61His (c.181G>C)?

AlphaMissense predicts likely pathogenic (score 0.9528) — an in-silico prediction, not a clinical call.

EPS15 p.Asp61His

c.181G>C · rs757458767 · VCV2526058

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9528 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9528	likely pathogenic · top 7% in EPS15
REVEL	0.49	indeterminate
SaProt	LLR -14.41	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	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

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EPS15
Protein: p.Asp61His
Coding: c.181G>C
MANE Select: NM_001981
dbSNP: rs757458767
Type: single nucleotide variant
Location: chr1:51471722 (GRCh38)
Gene constraint: LOEUF 0.849 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.60 · 13 PDB
Residue 61: the eh 1 domain; the 'interaction with dab2' region; the ef-hand 1 domain

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

Similar variants

EPS15 p.Asp61Asn Uncertain significance ★ ⚠ same residue
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

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-asp61his (accessed [today's date]).

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