Is EPHA8 p.Asp271Val (c.812A>T) pathogenic?

EPHA8 p.Asp271Val (c.812A>T) is classified Uncertain significance in EPHA8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-14). AlphaMissense: ambiguous (0.4217); Very rare (popmax 0.00225%, eas).

How common is EPHA8 p.Asp271Val (c.812A>T) in the general population?

EPHA8 p.Asp271Val (c.812A>T) is very rare (popmax 0.00225%, eas) (gnomAD).

What do computational predictors say about EPHA8 p.Asp271Val (c.812A>T)?

AlphaMissense predicts ambiguous (score 0.4217) — an in-silico prediction, not a clinical call.

EPHA8 p.Asp271Val

c.812A>T · VCV3845431

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4217 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00225%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4217	ambiguous
REVEL	0.656	pathogenic-leaning
SaProt	LLR -8.10	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 2.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 38 kb · p 0.015 · regional, not allelic
Overall
CADD	26.5	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 0.00225% East Asian · 1/44,506 alleles

Overall 6.95e-05% 1/1,439,398 alleles · very 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: EPHA8
Protein: p.Asp271Val
Coding: c.812A>T
MANE Select: NM_020526
Type: single nucleotide variant
Location: chr1:22576869 (GRCh38)
Gene constraint: LOEUF 0.717 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.63 · 3 PDB

Full EPHA8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPHA8 p.Gly93Ser Uncertain significance ★★ ⚠ same type
EPHA8 c.2538+11A>G Benign ★★ same type
EPHA8 p.Arg707Cys Benign ★★ ⚠ same type
EPHA8 p.Arg884His Likely benign ★★ ⚠ same type
EPHA8 p.Gly974= Benign ★★ same type
EPHA8 p.Leu211= Benign/Likely benign ★★ same type
EPHA8 p.Tyr508= Benign ★★ same type
EPHA8 p.Ala135Ser 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/epha8-p-asp271val (accessed [today's date]).

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