Is EPHA4 p.Pro328Ser (c.982C>T) pathogenic?

EPHA4 p.Pro328Ser (c.982C>T) is classified Uncertain significance in EPHA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-20). AlphaMissense: likely pathogenic (0.5835); Very rare (popmax 0.00539%, afr).

How common is EPHA4 p.Pro328Ser (c.982C>T) in the general population?

EPHA4 p.Pro328Ser (c.982C>T) is very rare (popmax 0.00539%, afr) (gnomAD).

What do computational predictors say about EPHA4 p.Pro328Ser (c.982C>T)?

AlphaMissense predicts likely pathogenic (score 0.5835) — an in-silico prediction, not a clinical call.

EPHA4 p.Pro328Ser

c.982C>T · rs1420416308 · VCV2255945

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5835 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00539%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5835	likely pathogenic
REVEL	0.446	indeterminate
SaProt	LLR -10.35	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 142 kb · p 2.7e-22 · regional, not allelic
Overall
CADD	29.2	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 0.00539% African / African-American · 4/74,244 alleles

Filtering AF 0.00176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00105%

Overall 0.00263% 4/152,124 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: EPHA4
Protein: p.Pro328Ser
Coding: c.982C>T
MANE Select: NM_004438
dbSNP: rs1420416308
Type: single nucleotide variant
Location: chr2:221482688 (GRCh38)
Gene constraint: LOEUF 0.256 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.93 · 17 PDB
Residue 328: the fibronectin type-iii 1 domain

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-pro328ser (accessed [today's date]).

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