Is EPHA5 p.Pro22Arg (c.65C>G) pathogenic?

EPHA5 p.Pro22Arg (c.65C>G) is classified Uncertain significance in EPHA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely benign (0.0819); Ultra-rare (popmax 0.0136%, afr).

How common is EPHA5 p.Pro22Arg (c.65C>G) in the general population?

EPHA5 p.Pro22Arg (c.65C>G) is ultra-rare (popmax 0.0136%, afr) (gnomAD).

What do computational predictors say about EPHA5 p.Pro22Arg (c.65C>G)?

AlphaMissense predicts likely benign (score 0.0819) — an in-silico prediction, not a clinical call.

EPHA5 p.Pro22Arg

c.65C>G · VCV4249824

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0819 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0136%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0819	likely benign
REVEL	0.032	moderately 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 -0.98, phastCons 0.14
Regional constraint	o/e 1.02	unconstrained · MANE · 68 kb · p 0.72 · regional, not allelic
Overall
CADD	20.1	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 0.0136% African / African-American · 9/66,342 alleles

Filtering AF 0.00706% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0052%

Overall 0.000824% 11/1,334,874 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0136%	7,371
European (non-Finnish)	0.000193%	519,219

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.Pro22Arg
Coding: c.65C>G
MANE Select: NM_001281766
Type: single nucleotide variant
Location: chr4:65669678 (GRCh38)
Gene constraint: LOEUF 0.711 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.10 · 2 PDB
Residue 22: the 'disordered' region

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-pro22arg (accessed [today's date]).

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