Is EPHA7 p.Pro655Arg (c.1964C>G) pathogenic?

EPHA7 p.Pro655Arg (c.1964C>G) is classified Uncertain significance in EPHA7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-17). AlphaMissense: ambiguous (0.3853); Very rare (popmax 0.000509%, nfe).

How common is EPHA7 p.Pro655Arg (c.1964C>G) in the general population?

EPHA7 p.Pro655Arg (c.1964C>G) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about EPHA7 p.Pro655Arg (c.1964C>G)?

AlphaMissense predicts ambiguous (score 0.3853) — an in-silico prediction, not a clinical call.

EPHA7 p.Pro655Arg

c.1964C>G · rs1316144079 · VCV3089617

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3853 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3853	ambiguous
REVEL	0.575	indeterminate
SaProt	LLR -14.55	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 115 kb · p 1.6e-06 · regional, not allelic
Overall
CADD	29.3	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

Grpmax group 0.000509% European (non-Finnish) · 6/1,178,170 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000373% 6/1,610,332 alleles · very rare

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: EPHA7
Protein: p.Pro655Arg
Coding: c.1964C>G
MANE Select: NM_004440
dbSNP: rs1316144079
Type: single nucleotide variant
Location: chr6:93258245 (GRCh38)
Gene constraint: LOEUF 0.282 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 82.09 · 7 PDB
Residue 655: a β-strand; the protein kinase domain

Full EPHA7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPHA7 p.Pro655Ala Uncertain significance ★ ⚠ same residue
EPHA7 c.2111-2A>G Uncertain significance ★ same type
EPHA7 p.Ala191Ser Uncertain significance ★ ⚠ same type
EPHA7 p.Ala27Glu Uncertain significance ★ ⚠ same type
EPHA7 p.Ala520Asp Uncertain significance ★ ⚠ same type
EPHA7 p.Ala721Ser Uncertain significance ★ ⚠ same type
EPHA7 p.Ala721Val Uncertain significance ★ ⚠ same type
EPHA7 p.Ala761Val 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/epha7-p-pro655arg (accessed [today's date]).

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