Is EPHA5 p.Val992Ile (c.2974G>A) pathogenic?

EPHA5 p.Val992Ile (c.2974G>A) is classified Uncertain significance in EPHA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-14). AlphaMissense: likely benign (0.0907); Very rare (popmax 0.00269%, afr).

How common is EPHA5 p.Val992Ile (c.2974G>A) in the general population?

EPHA5 p.Val992Ile (c.2974G>A) is very rare (popmax 0.00269%, afr) (gnomAD).

What do computational predictors say about EPHA5 p.Val992Ile (c.2974G>A)?

AlphaMissense predicts likely benign (score 0.0907) — an in-silico prediction, not a clinical call.

EPHA5 p.Val992Ile

c.2974G>A · rs1203055827 · VCV2495983

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0907 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00269%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0907	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -3.36	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 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 278 kb · p 0.18 · regional, not allelic
Overall
CADD	22.2	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V1013I vs ClinVar V992I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00269% African / African-American · 2/74,482 alleles

Filtering AF 0.000446% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000167%

Overall 0.000186% 3/1,609,334 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00269%	37,241
European (non-Finnish)	8.5e-05%	1,176,972

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: EPHA5
Protein: p.Val992Ile
Coding: c.2974G>A
MANE Select: NM_001281766
dbSNP: rs1203055827
Type: single nucleotide variant
Location: chr4:65324191 (GRCh38)
Gene constraint: LOEUF 0.711 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.10 · 2 PDB
Residue 992: the sam domain

Full EPHA5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPHA5 c.2173+8T>A Benign ★★ same type
EPHA5 p.Ala646= Benign ★★ same type
EPHA5 p.Glu528Gln Benign ★★ ⚠ same type
EPHA5 p.Ser652Thr Likely benign ★★ ⚠ same type
EPHA5 c.1794-9583G>A Uncertain significance ★ ⚠ same type
EPHA5 c.1794-9635T>G Uncertain significance ★ ⚠ same type
EPHA5 p.Ala123Val Uncertain significance ★ ⚠ same type
EPHA5 p.Ala332Gly 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/epha5-p-val992ile (accessed [today's date]).

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