Is EPHA2 p.Pro63= (c.189G>A) pathogenic?

EPHA2 p.Pro63= (c.189G>A) is classified Likely benign in EPHA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-12). Ultra-rare (popmax 0.0134%, eas); Associated with Inborn genetic diseases.

What condition is associated with EPHA2 p.Pro63= (c.189G>A)?

EPHA2 p.Pro63= (c.189G>A) is associated with Inborn genetic diseases (ClinVar).

How common is EPHA2 p.Pro63= (c.189G>A) in the general population?

EPHA2 p.Pro63= (c.189G>A) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

EPHA2 p.Pro63=

c.189G>A · VCV4841193

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.6	GERP 0.027, phastCons 1
Overall
CADD	12.24	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,890 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00471% 76/1,613,860 alleles · ultra-rare exomes 69/1,461,566 · genomes 7/152,294 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,482
African / African-American	0.00533%	18,760
European (non-Finnish)	0.00517%	19,345
Remaining individualsnot grpmax-eligible	0.0048%	20,835
South Asian	0.0022%	45,535

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: EPHA2
Protein: p.Pro63=
Coding: c.189G>A
MANE Select: NM_004431
Type: single nucleotide variant
Location: chr1:16149012 (GRCh38)
Gene constraint: LOEUF 0.652 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.73 · 103 PDB
Residue 63: the 'mediates interaction with cldn4' region; the eph lbd domain

Full EPHA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPHA2 p.Pro63Leu Uncertain significance ★ ⚠ same residue
EPHA2 p.Pro63Thr Uncertain significance ★ ⚠ same residue
EPHA2 p.Arg315Trp Uncertain significance ★★ ⚠ same condition
EPHA2 p.Arg560His Uncertain significance ★★ ⚠ same condition
EPHA2 p.Arg566His Uncertain significance ★★ ⚠ same condition
EPHA2 p.Arg677Cys Uncertain significance ★★ ⚠ same condition
EPHA2 p.Asp148Asn Uncertain significance ★★ ⚠ same condition
EPHA2 p.Asp888Asn Uncertain significance ★★ ⚠ same condition

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/epha2-p-pro63 (accessed [today's date]).

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