Is EPHB4 p.Val219Met (c.655G>A) pathogenic?

EPHB4 p.Val219Met (c.655G>A) is classified Uncertain significance in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-23). AlphaMissense: ambiguous (0.4702); Very rare (popmax 0.00535%, afr); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Val219Met (c.655G>A)?

EPHB4 p.Val219Met (c.655G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Val219Met (c.655G>A) in the general population?

EPHB4 p.Val219Met (c.655G>A) is very rare (popmax 0.00535%, afr) (gnomAD).

What do computational predictors say about EPHB4 p.Val219Met (c.655G>A)?

AlphaMissense predicts ambiguous (score 0.4702) — an in-silico prediction, not a clinical call.

EPHB4 p.Val219Met

c.655G>A · rs761954921 · VCV1754190

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4702 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00535%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4702	ambiguous
REVEL	0.486	indeterminate
SaProt	LLR -10.46	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00535% African / African-American · 4/74,726 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000877% 14/1,597,160 alleles · very rare exomes 12/1,444,932 · genomes 2/152,228 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00535%	18,681
Remaining individualsnot grpmax-eligible	0.00162%	61,726
European (non-Finnish)	0.000769%	130,029

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.Val219Met
Coding: c.655G>A
MANE Select: NM_004444
dbSNP: rs761954921
Type: single nucleotide variant
Location: chr7:100822424 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 219: 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-val219met (accessed [today's date]).

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