Is EPHB4 p.Arg362= (c.1086G>C) pathogenic?

EPHB4 p.Arg362= (c.1086G>C) is classified Likely benign in EPHB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-12-07). Ultra-rare (popmax 0.0141%, amr); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Arg362= (c.1086G>C)?

EPHB4 p.Arg362= (c.1086G>C) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Arg362= (c.1086G>C) in the general population?

EPHB4 p.Arg362= (c.1086G>C) is ultra-rare (popmax 0.0141%, amr) (gnomAD).

EPHB4 p.Arg362=

c.1086G>C · rs535100667 · VCV1787761

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0141%, amr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.88 · evaluated, not missing
Constraint at this position
Conservation	phyloP -6.7	GERP -5
Overall
CADD	0.479	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0141% Admixed American · 8/56,596 alleles

Filtering AF 0.00696% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00507%

Overall 0.001% 16/1,595,812 alleles · ultra-rare exomes 11/1,443,470 · genomes 5/152,342 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0141%	7,074
South Asian	0.00783%	12,775
European (non-Finnish)	8.54e-05%	1,171,589

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: EPHB4
Protein: p.Arg362=
Coding: c.1086G>C
MANE Select: NM_004444
dbSNP: rs535100667
Type: single nucleotide variant
Location: chr7:100819768 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 362: a UniProt-annotated variant site (in cmavm2); the fibronectin type-iii 1 domain

Full EPHB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPHB4 p.Arg362Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
EPHB4 p.Arg362Gln Likely benign ★ same residue
EPHB4 c.1870+5G>C Uncertain significance ★★ same condition
EPHB4 p.Ala262Val Uncertain significance ★★ ⚠ same condition
EPHB4 p.Ala345Gly Uncertain significance ★★ ⚠ same condition
EPHB4 p.Ala931Thr Uncertain significance ★★ ⚠ same condition
EPHB4 p.Arg148Trp Uncertain significance ★★ ⚠ same condition
EPHB4 p.Arg310Gln 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/ephb4-p-arg362 (accessed [today's date]).

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