Is EPHB4 p.Ala220= (c.660C>T) pathogenic?

EPHB4 p.Ala220= (c.660C>T) is classified Likely benign in EPHB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-04-26). Very rare (popmax 0.00337%, sas); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Ala220= (c.660C>T)?

EPHB4 p.Ala220= (c.660C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Ala220= (c.660C>T) in the general population?

EPHB4 p.Ala220= (c.660C>T) is very rare (popmax 0.00337%, sas) (gnomAD).

EPHB4 p.Ala220=

c.660C>T · rs200580904 · VCV1754456

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00337%, sas)

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 · G>T here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP -13	GERP -4.8
Overall
CADD	0.092	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00337% South Asian · 3/89,084 alleles

Filtering AF 0.000895% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000448%

Overall 0.000627% 10/1,594,330 alleles · very rare exomes 8/1,442,010 · genomes 2/152,320 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00337%	29,695
East Asian	0.00225%	44,354
Admixed American	0.00174%	57,542
European (non-Finnish)	0.000428%	233,779

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.Ala220=
Coding: c.660C>T
MANE Select: NM_004444
dbSNP: rs200580904
Type: single nucleotide variant
Location: chr7:100822419 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 220: 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 p.Ala220Ser Uncertain significance ★ ⚠ 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
EPHB4 p.Arg483Gln 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-ala220 (accessed [today's date]).

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