Is EPS8 p.Asp278Val (c.833A>T) pathogenic?

EPS8 p.Asp278Val (c.833A>T) is classified Uncertain significance in EPS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-25). AlphaMissense: likely pathogenic (0.9713); Ultra-rare (popmax 0.0111%, sas).

How common is EPS8 p.Asp278Val (c.833A>T) in the general population?

EPS8 p.Asp278Val (c.833A>T) is ultra-rare (popmax 0.0111%, sas) (gnomAD).

What do computational predictors say about EPS8 p.Asp278Val (c.833A>T)?

AlphaMissense predicts likely pathogenic (score 0.9713) — an in-silico prediction, not a clinical call.

EPS8 p.Asp278Val

c.833A>T · VCV4540051

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9713 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9713	likely pathogenic · top 9% in EPS8
REVEL	0.729	pathogenic-leaning
SaProt	LLR -15.17	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.24	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 7.8	GERP 2.5, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 62 kb · p 0.26 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 0.0111% South Asian · 10/90,204 alleles

Filtering AF 0.00599% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00457%

Overall 0.000688% 10/1,453,072 alleles · ultra-rare

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: EPS8
Protein: p.Asp278Val
Coding: c.833A>T
MANE Select: NM_004447
Type: single nucleotide variant
Location: chr12:15660718 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 70.77 · 2 PDB

Full EPS8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPS8 c.205-8A>G Uncertain significance ★★ same type
EPS8 p.Ala150Val Uncertain significance ★★ ⚠ same type
EPS8 p.Ala219Val Uncertain significance ★★ ⚠ same type
EPS8 p.Ala416Asp Uncertain significance ★★ ⚠ same type
EPS8 p.Arg195Trp Uncertain significance ★★ ⚠ same type
EPS8 p.Arg403Trp Uncertain significance ★★ ⚠ same type
EPS8 p.Arg432Gln Uncertain significance ★★ ⚠ same type
EPS8 p.Arg434Cys 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/eps8-p-asp278val (accessed [today's date]).

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