Is EPHA2 p.Val641Ala (c.1922T>C) pathogenic?

EPHA2 p.Val641Ala (c.1922T>C) is classified Uncertain significance in EPHA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-02). AlphaMissense: likely benign (0.151); Ultra-rare (popmax 0.0933%, sas); Associated with Inborn genetic diseases.

What condition is associated with EPHA2 p.Val641Ala (c.1922T>C)?

EPHA2 p.Val641Ala (c.1922T>C) is associated with Inborn genetic diseases (ClinVar).

How common is EPHA2 p.Val641Ala (c.1922T>C) in the general population?

EPHA2 p.Val641Ala (c.1922T>C) is ultra-rare (popmax 0.0933%, sas) (gnomAD).

What do computational predictors say about EPHA2 p.Val641Ala (c.1922T>C)?

AlphaMissense predicts likely benign (score 0.151) — an in-silico prediction, not a clinical call.

EPHA2 p.Val641Ala

c.1922T>C · VCV3509274

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.151 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0933%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.151	likely benign
REVEL	0.385	indeterminate
SaProt	LLR -10.30	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 2.2, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 1,159 bp · p 0.39 · regional, not allelic
Overall
CADD	23.4	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 0.0933% South Asian · 85/91,082 alleles

Filtering AF 0.0773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0713%

Overall 0.00552% 89/1,613,720 alleles · ultra-rare exomes 85/1,461,624 · genomes 4/152,096 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0933%	1,072
Remaining individualsnot grpmax-eligible	0.0032%	31,250
Admixed American	0.00167%	59,992
European (non-Finnish)	8.48e-05%	1,179,916

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: EPHA2
Protein: p.Val641Ala
Coding: c.1922T>C
MANE Select: NM_004431
Type: single nucleotide variant
Location: chr1:16133311 (GRCh38)
Gene constraint: LOEUF 0.652 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.73 · 103 PDB
Residue 641: the 'mediates interaction with arhgef16 and elmo2' region; a β-strand; the protein kinase domain

Full EPHA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPHA2 p.Arg315Trp Uncertain significance ★★ ⚠ same condition
EPHA2 p.Arg560His Uncertain significance ★★ ⚠ same condition
EPHA2 p.Arg566His Uncertain significance ★★ ⚠ same condition
EPHA2 p.Arg677Cys Uncertain significance ★★ ⚠ same condition
EPHA2 p.Asp148Asn Uncertain significance ★★ ⚠ same condition
EPHA2 p.Asp888Asn Uncertain significance ★★ ⚠ same condition
EPHA2 p.Cys309Arg Uncertain significance ★★ ⚠ same condition
EPHA2 p.Gly217Ser Uncertain significance ★★ ⚠ same condition

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/epha2-p-val641ala (accessed [today's date]).

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