Is EPHA8 p.Pro466Ser (c.1396C>T) pathogenic?

EPHA8 p.Pro466Ser (c.1396C>T) is classified Uncertain significance in EPHA8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-04). AlphaMissense: likely pathogenic (0.6598); Very rare (popmax 0.00456%, eas).

How common is EPHA8 p.Pro466Ser (c.1396C>T) in the general population?

EPHA8 p.Pro466Ser (c.1396C>T) is very rare (popmax 0.00456%, eas) (gnomAD).

What do computational predictors say about EPHA8 p.Pro466Ser (c.1396C>T)?

AlphaMissense predicts likely pathogenic (score 0.6598) — an in-silico prediction, not a clinical call.

EPHA8 p.Pro466Ser

c.1396C>T · rs756827993 · VCV3089631

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6598 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00456%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6598	likely pathogenic
REVEL	0.338	indeterminate
SaProt	LLR -7.11	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 38 kb · p 0.015 · regional, not allelic
Overall
CADD	25.6	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 0.00456% East Asian · 2/43,850 alleles

Filtering AF 0.000756% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000283%

Overall 0.000125% 2/1,593,664 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.Pro466Ser
Coding: c.1396C>T
MANE Select: NM_020526
dbSNP: rs756827993
Type: single nucleotide variant
Location: chr1:22593406 (GRCh38)
Gene constraint: LOEUF 0.717 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.63 · 3 PDB
Residue 466: the fibronectin type-iii 2 domain

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

Similar variants

EPHA8 p.Pro466Leu Uncertain significance ★ ⚠ same residue
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

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-pro466ser (accessed [today's date]).

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