Is EPHB4 p.Ile886= (c.2658C>T) pathogenic?

EPHB4 p.Ile886= (c.2658C>T) is classified Benign/Likely benign in EPHB4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-14). Low-frequency (popmax 2.35%, afr); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Ile886= (c.2658C>T)?

EPHB4 p.Ile886= (c.2658C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Ile886= (c.2658C>T) in the general population?

EPHB4 p.Ile886= (c.2658C>T) is low-frequency (popmax 2.35%, afr) (gnomAD).

EPHB4 p.Ile886=

c.2658C>T · rs149061889 · VCV708483

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.35%, afr)

Conditions

Cardiovascular phenotype

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 -2.5	GERP -4.6
Overall
CADD	7.41	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.35% African / African-American · 1,696/72,024 alleles

Filtering AF 2.26% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.22%

Overall 0.131% 2,000/1,522,276 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.35%	42
Middle Eastern	0.282%	355
Admixed American	0.219%	456
Remaining individualsnot grpmax-eligible	0.178%	562
European (non-Finnish)	0.00714%	14,012
South Asian	0.00524%	19,099

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.Ile886=
Coding: c.2658C>T
MANE Select: NM_004444
dbSNP: rs149061889
Type: single nucleotide variant
Location: chr7:100805521 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 886: a UniProt-annotated variant site (in cmavm2); the protein kinase 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 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
EPHB4 p.Arg483Gln Uncertain significance ★★ ⚠ same condition
EPHB4 p.Arg499Gln 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-ile886 (accessed [today's date]).

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