Is EPHA8 p.Arg653Ser (c.1959G>T) pathogenic?

EPHA8 p.Arg653Ser (c.1959G>T) is classified Uncertain significance in EPHA8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-18). AlphaMissense: likely benign (0.3007); Absent from gnomAD v4.1.

How common is EPHA8 p.Arg653Ser (c.1959G>T) in the general population?

EPHA8 p.Arg653Ser (c.1959G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EPHA8 p.Arg653Ser (c.1959G>T)?

AlphaMissense predicts likely benign (score 0.3007) — an in-silico prediction, not a clinical call.

EPHA8 p.Arg653Ser

c.1959G>T · VCV4664772

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3007 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3007	likely benign
REVEL	0.303	indeterminate
SaProt	LLR -10.69	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.24	GERP -3.6, phastCons 0.021
Regional constraint	o/e 0.93	unconstrained · MANE · 38 kb · p 0.015 · regional, not allelic
Overall
CADD	21.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EPHA8
Protein: p.Arg653Ser
Coding: c.1959G>T
MANE Select: NM_020526
Type: single nucleotide variant
Location: chr1:22597704 (GRCh38)
Gene constraint: LOEUF 0.717 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.63 · 3 PDB
Residue 653: a β-strand; the protein kinase domain

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-arg653ser (accessed [today's date]).

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