Is EPHA4 p.Pro680= (c.2040G>A) pathogenic?

EPHA4 p.Pro680= (c.2040G>A) is classified Likely benign in EPHA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-07). Ultra-rare (popmax 0.0133%, afr).

How common is EPHA4 p.Pro680= (c.2040G>A) in the general population?

EPHA4 p.Pro680= (c.2040G>A) is ultra-rare (popmax 0.0133%, afr) (gnomAD).

EPHA4 p.Pro680=

c.2040G>A · rs113258181 · VCV1606910

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.8	GERP -5.5
Overall
CADD	0.965	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% African / African-American · 10/75,018 alleles

Filtering AF 0.00722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00549%

Overall 0.00142% 23/1,614,126 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.016%	6,251
African / African-Americangrpmax	0.0133%	7,502
Admixed American	0.00167%	60,024
South Asian	0.0011%	91,074
European (non-Finnish)	8.47e-05%	1,180,012

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: EPHA4
Protein: p.Pro680=
Coding: c.2040G>A
MANE Select: NM_004438
dbSNP: rs113258181
Type: single nucleotide variant
Location: chr2:221442863 (GRCh38)
Gene constraint: LOEUF 0.256 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.93 · 17 PDB
Residue 680: the protein kinase domain

Full EPHA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPHA4 p.Ala321Thr Uncertain significance ★★ ⚠ same type
EPHA4 p.Ala852Val Uncertain significance ★★ ⚠ same type
EPHA4 p.Arg209Cys Uncertain significance ★★ ⚠ same type
EPHA4 p.Arg230Gln Uncertain significance ★★ ⚠ same type
EPHA4 p.Arg466Gln Uncertain significance ★★ ⚠ same type
EPHA4 p.Arg466Trp Uncertain significance ★★ ⚠ same type
EPHA4 p.Arg486Gln Uncertain significance ★★ ⚠ same type
EPHA4 p.Arg573Trp 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/epha4-p-pro680 (accessed [today's date]).

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