Is EPHA8 p.Arg269Gln (c.806G>A) pathogenic?

EPHA8 p.Arg269Gln (c.806G>A) is classified Uncertain significance in EPHA8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-21). AlphaMissense: likely benign (0.0703); Rare (popmax 0.102%, afr).

How common is EPHA8 p.Arg269Gln (c.806G>A) in the general population?

EPHA8 p.Arg269Gln (c.806G>A) is rare (popmax 0.102%, afr) (gnomAD).

What do computational predictors say about EPHA8 p.Arg269Gln (c.806G>A)?

AlphaMissense predicts likely benign (score 0.0703) — an in-silico prediction, not a clinical call.

EPHA8 p.Arg269Gln

c.806G>A · rs139777546 · VCV2596400

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0703 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.102%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0703	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -6.45	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 1.1	GERP -1.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 38 kb · p 0.015 · regional, not allelic
Overall
CADD	18.91	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 0.102% African / African-American · 76/74,758 alleles

Filtering AF 0.0832% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0765%

Overall 0.00502% 80/1,594,810 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.102%	984
Remaining individualsnot grpmax-eligible	0.00488%	20,484
European (non-Finnish)	8.56e-05%	1,168,501

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: EPHA8
Protein: p.Arg269Gln
Coding: c.806G>A
MANE Select: NM_020526
dbSNP: rs139777546
Type: single nucleotide variant
Location: chr1:22576863 (GRCh38)
Gene constraint: LOEUF 0.717 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.63 · 3 PDB

Full EPHA8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPHA8 p.Gly93Ser Uncertain significance ★★ ⚠ same type
EPHA8 c.2538+11A>G Benign ★★ same type
EPHA8 p.Arg707Cys Benign ★★ ⚠ same type
EPHA8 p.Arg884His Likely benign ★★ ⚠ same type
EPHA8 p.Gly974= Benign ★★ same type
EPHA8 p.Leu211= Benign/Likely benign ★★ same type
EPHA8 p.Tyr508= Benign ★★ same type
EPHA8 p.Ala135Ser 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/epha8-p-arg269gln (accessed [today's date]).

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