Is EPHB4 p.Arg444Leu (c.1331G>T) pathogenic?

EPHB4 p.Arg444Leu (c.1331G>T) is classified Likely benign in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-13). AlphaMissense: likely benign (0.1784); Very rare (popmax 0.0089%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Arg444Leu (c.1331G>T)?

EPHB4 p.Arg444Leu (c.1331G>T) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Arg444Leu (c.1331G>T) in the general population?

EPHB4 p.Arg444Leu (c.1331G>T) is very rare (popmax 0.0089%, nfe) (gnomAD).

What do computational predictors say about EPHB4 p.Arg444Leu (c.1331G>T)?

AlphaMissense predicts likely benign (score 0.1784) — an in-silico prediction, not a clinical call.

EPHB4 p.Arg444Leu

c.1331G>T · rs146064780 · VCV2466651

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1784 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0089%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1784	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -9.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.20	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 7.7	GERP 1, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	22.0	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 0.0089% European (non-Finnish) · 105/1,179,982 alleles

Filtering AF 0.00749% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.007%

Overall 0.00664% 107/1,612,568 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0089%	11,238
Admixed American	0.00167%	59,978
African / African-American	0.00134%	74,896

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.Arg444Leu
Coding: c.1331G>T
MANE Select: NM_004444
dbSNP: rs146064780
Type: single nucleotide variant
Location: chr7:100818611 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 444: a β-strand; a UniProt-annotated variant site (in cmavm2); the fibronectin type-iii 2 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.Arg444Trp 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-arg444leu (accessed [today's date]).

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