Is EPHA1 p.Val164Ala (c.491T>C) pathogenic?

EPHA1 p.Val164Ala (c.491T>C) is classified Uncertain significance in EPHA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-22). AlphaMissense: likely benign (0.1521); Very rare (popmax 0.00746%, nfe).

How common is EPHA1 p.Val164Ala (c.491T>C) in the general population?

EPHA1 p.Val164Ala (c.491T>C) is very rare (popmax 0.00746%, nfe) (gnomAD).

What do computational predictors say about EPHA1 p.Val164Ala (c.491T>C)?

AlphaMissense predicts likely benign (score 0.1521) — an in-silico prediction, not a clinical call.

EPHA1 p.Val164Ala

c.491T>C · rs751226403 · VCV2342765

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1521 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00746%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1521	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -7.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 4.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 17 kb · p 0.023 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00746% European (non-Finnish) · 88/1,179,910 alleles

Filtering AF 0.00615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00573%

Overall 0.00576% 93/1,613,712 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00746%	13,408
African / African-American	0.004%	24,982
Admixed American	0.00333%	30,001

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: EPHA1
Protein: p.Val164Ala
Coding: c.491T>C
MANE Select: NM_005232
dbSNP: rs751226403
Type: single nucleotide variant
Location: chr7:143399995 (GRCh38)
Gene constraint: LOEUF 0.989 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.74 · 4 PDB
Residue 164: the eph lbd domain

Full EPHA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPHA1 c.835+8C>T Benign ★★ same type
EPHA1 p.Ala23= Benign ★★ same type
EPHA1 p.Arg24His Benign ★★ ⚠ same type
EPHA1 p.Glu314= Benign ★★ same type
EPHA1 p.His872= Benign ★★ same type
EPHA1 p.His963= Benign ★★ same type
EPHA1 p.Ala184Val Uncertain significance ★ ⚠ same type
EPHA1 p.Ala212Ser 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/epha1-p-val164ala (accessed [today's date]).

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