Is EPHA8 p.Arg537Cys (c.1609C>T) pathogenic?

EPHA8 p.Arg537Cys (c.1609C>T) is classified Uncertain significance in EPHA8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: likely benign (0.2339); Ultra-rare (popmax 0.0172%, nfe).

How common is EPHA8 p.Arg537Cys (c.1609C>T) in the general population?

EPHA8 p.Arg537Cys (c.1609C>T) is ultra-rare (popmax 0.0172%, nfe) (gnomAD).

What do computational predictors say about EPHA8 p.Arg537Cys (c.1609C>T)?

AlphaMissense predicts likely benign (score 0.2339) — an in-silico prediction, not a clinical call.

EPHA8 p.Arg537Cys

c.1609C>T · VCV4664765

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2339 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0172%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2339	likely benign
REVEL	0.288	benign-leaning
SaProt	LLR -8.85	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 4.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 38 kb · p 0.015 · regional, not allelic
Overall
CADD	25.9	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 0.0172% European (non-Finnish) · 202/1,176,930 alleles

Filtering AF 0.0152% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0144%

Overall 0.013% 209/1,609,488 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0172%	5,826
Remaining individualsnot grpmax-eligible	0.00482%	20,742
African / African-American	0.00267%	37,408
Admixed American	0.00167%	59,870
South Asian	0.0011%	90,636

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.Arg537Cys
Coding: c.1609C>T
MANE Select: NM_020526
Type: single nucleotide variant
Location: chr1:22595235 (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.Arg537Gly Uncertain significance ★ ⚠ same residue
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

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-arg537cys (accessed [today's date]).

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