Is EPS15 p.Ala4Thr (c.10G>A) pathogenic?

EPS15 p.Ala4Thr (c.10G>A) is classified Uncertain significance in EPS15 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-10). AlphaMissense: ambiguous (0.4197); Ultra-rare (popmax 0.0204%, mid).

How common is EPS15 p.Ala4Thr (c.10G>A) in the general population?

EPS15 p.Ala4Thr (c.10G>A) is ultra-rare (popmax 0.0204%, mid) (gnomAD).

What do computational predictors say about EPS15 p.Ala4Thr (c.10G>A)?

AlphaMissense predicts ambiguous (score 0.4197) — an in-silico prediction, not a clinical call.

EPS15 p.Ala4Thr

c.10G>A · rs140274886 · VCV3089892

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4197 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0204%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4197	ambiguous
REVEL	0.071	moderately benign-leaning
SaProt	LLR -8.02	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.3	GERP 1.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 163 kb · p 0.94 · regional, not allelic
Overall
CADD	24.0	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 0.0204% Middle Eastern · 1/4,914 alleles

Filtering AF 0.00415% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00379%

Overall 0.00439% 62/1,413,492 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0204%	4,914
Remaining individualsnot grpmax-eligible	0.00578%	17,303
European (non-Finnish)	0.00531%	18,822
Finnishnot grpmax-eligible	0.0018%	55,702

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.Ala4Thr
Coding: c.10G>A
MANE Select: NM_001981
dbSNP: rs140274886
Type: single nucleotide variant
Location: chr1:51519222 (GRCh38)
Gene constraint: LOEUF 0.849 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.60 · 13 PDB
Residue 4: the 'interaction with dab2' region

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.Ala560Ser Uncertain significance ★ ⚠ same type
EPS15 p.Ala613Gly Uncertain significance ★ ⚠ same type
EPS15 p.Ala667Thr Uncertain significance ★ ⚠ same type
EPS15 p.Ala676Val 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-ala4thr (accessed [today's date]).

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