Is EPHB4 p.Cys223= (c.669C>T) pathogenic?

EPHB4 p.Cys223= (c.669C>T) is classified Likely benign in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-01). Very rare (popmax 0.00178%, amr); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Cys223= (c.669C>T)?

EPHB4 p.Cys223= (c.669C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Cys223= (c.669C>T) in the general population?

EPHB4 p.Cys223= (c.669C>T) is very rare (popmax 0.00178%, amr) (gnomAD).

EPHB4 p.Cys223=

c.669C>T · rs937992856 · VCV2565142

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00178%, amr)

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 -1	GERP -4.8
Overall
CADD	2.73	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00178% Admixed American · 1/56,050 alleles

Filtering AF 0.000507% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00037%

Overall 0.00101% 16/1,586,368 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00326%	30,687
Admixed Americangrpmax	0.00178%	56,050
African / African-American	0.00134%	74,646
South Asian	0.00113%	88,454
European (non-Finnish)	0.000944%	105,885

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: EPHB4
Protein: p.Cys223=
Coding: c.669C>T
MANE Select: NM_004444
dbSNP: rs937992856
Type: single nucleotide variant
Location: chr7:100822410 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 223: a UniProt-annotated variant site (in cmavm2)

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-cys223 (accessed [today's date]).

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