Is EPHB4 p.Arg397His (c.1190G>A) pathogenic?

EPHB4 p.Arg397His (c.1190G>A) is classified Conflicting classifications of pathogenicity in EPHB4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-12-05). AlphaMissense: likely benign (0.1201); Very rare (popmax 0.00667%, amr); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Arg397His (c.1190G>A)?

EPHB4 p.Arg397His (c.1190G>A) is associated with Cardiovascular phenotype, capillary malformation-arteriovenous malformation 2 (ClinVar).

How common is EPHB4 p.Arg397His (c.1190G>A) in the general population?

EPHB4 p.Arg397His (c.1190G>A) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about EPHB4 p.Arg397His (c.1190G>A)?

AlphaMissense predicts likely benign (score 0.1201) — an in-silico prediction, not a clinical call.

EPHB4 p.Arg397His

c.1190G>A · rs538766032 · VCV1693572

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1201 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1201	likely benign
REVEL	0.287	benign-leaning
SaProt	LLR -7.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP -1.3, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	25.8	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 0.00667% Admixed American · 4/60,006 alleles

Filtering AF 0.00342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.00366% 59/1,613,758 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,002
European (non-Finnish)	0.00441%	22,691
East Asian	0.00223%	44,872
Remaining individualsnot grpmax-eligible	0.0016%	62,480
South Asian	0.0011%	91,062

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.Arg397His
Coding: c.1190G>A
MANE Select: NM_004444
dbSNP: rs538766032
Type: single nucleotide variant
Location: chr7:100819664 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 397: a UniProt-annotated variant site (in cmavm2); the fibronectin type-iii 1 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

Also linked: capillary malformation-arteriovenous malformation 2

Similar variants

EPHB4 p.Arg397Cys Likely benign ★ ⚠ same residue
EPHB4 c.2484+1G>A Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Arg365Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Arg739Ter Pathogenic ★★ same condition
EPHB4 p.Arg763Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Gln580Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Glu664Lys Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Trp72Ter Pathogenic/Likely pathogenic ★★ 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-arg397his (accessed [today's date]).

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