Is EPHA4 p.Ser232Phe (c.695C>T) pathogenic?

EPHA4 p.Ser232Phe (c.695C>T) is classified Uncertain significance in EPHA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: likely benign (0.117); Absent from gnomAD v4.1.

How common is EPHA4 p.Ser232Phe (c.695C>T) in the general population?

EPHA4 p.Ser232Phe (c.695C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EPHA4 p.Ser232Phe (c.695C>T)?

AlphaMissense predicts likely benign (score 0.117) — an in-silico prediction, not a clinical call.

EPHA4 p.Ser232Phe

c.695C>T · VCV4664721

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.117 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.117	likely benign
REVEL	0.658	pathogenic-leaning
SaProt	LLR -10.43	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 142 kb · p 2.7e-22 · regional, not allelic
Overall
CADD	29.8	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

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: EPHA4
Protein: p.Ser232Phe
Coding: c.695C>T
MANE Select: NM_004438
Type: single nucleotide variant
Location: chr2:221563859 (GRCh38)
Gene constraint: LOEUF 0.256 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.93 · 17 PDB

Full EPHA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPHA4 p.Ala321Thr Uncertain significance ★★ ⚠ same type
EPHA4 p.Ala852Val Uncertain significance ★★ ⚠ same type
EPHA4 p.Arg209Cys Uncertain significance ★★ ⚠ same type
EPHA4 p.Arg230Gln Uncertain significance ★★ ⚠ same type
EPHA4 p.Arg466Gln Uncertain significance ★★ ⚠ same type
EPHA4 p.Arg466Trp Uncertain significance ★★ ⚠ same type
EPHA4 p.Arg486Gln Uncertain significance ★★ ⚠ same type
EPHA4 p.Arg573Trp 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/epha4-p-ser232phe (accessed [today's date]).

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