Is EPHB4 p.Arg744His (c.2231G>A) pathogenic?

EPHB4 p.Arg744His (c.2231G>A) is classified Conflicting classifications of pathogenicity in EPHB4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-05-22). AlphaMissense: likely pathogenic (0.9977); Very rare (popmax 8.47e-05%, nfe); Associated with Incidental Discovery.

What condition is associated with EPHB4 p.Arg744His (c.2231G>A)?

EPHB4 p.Arg744His (c.2231G>A) is associated with Incidental Discovery, lymphatic malformation 7, capillary malformation-arteriovenous malformation 2 (ClinVar).

How common is EPHB4 p.Arg744His (c.2231G>A) in the general population?

EPHB4 p.Arg744His (c.2231G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about EPHB4 p.Arg744His (c.2231G>A)?

AlphaMissense predicts likely pathogenic (score 0.9977) — an in-silico prediction, not a clinical call.

EPHB4 p.Arg744His

c.2231G>A · VCV3600344

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Incidental Discovery

Computational evidence

Protein change
AlphaMissense	0.9977	likely pathogenic · top 8% in EPHB4
REVEL	0.881	moderately pathogenic-leaning
SaProt	LLR -14.40	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 6,734 bp · p 5.4e-12 · regional, not allelic
Overall
CADD	33.0	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 8.47e-05% European (non-Finnish) · 1/1,179,988 alleles

Overall 6.84e-05% 1/1,461,868 alleles · very rare

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.Arg744His
Coding: c.2231G>A
MANE Select: NM_004444
Type: single nucleotide variant
Location: chr7:100807468 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 744: an α-helix; a UniProt-annotated variant site (in cmavm2); the protein kinase domain

Full EPHB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Incidental Discovery — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: lymphatic malformation 7 capillary malformation-arteriovenous malformation 2

Similar variants

EPHB4 p.Arg744Cys Uncertain significance ★ ⚠ same residue
EPHB4 c.2484+1G>A Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Arg365Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Arg739Gln 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

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-arg744his (accessed [today's date]).

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