Is EPHB4 p.Arg431Ter (c.1291C>T) pathogenic?

EPHB4 p.Arg431Ter (c.1291C>T) is classified Pathogenic in EPHB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-21). Very rare (popmax 0.0018%, amr); Associated with capillary malformation-arteriovenous malformation syndrome.

What condition is associated with EPHB4 p.Arg431Ter (c.1291C>T)?

EPHB4 p.Arg431Ter (c.1291C>T) is associated with capillary malformation-arteriovenous malformation syndrome (ClinVar).

How common is EPHB4 p.Arg431Ter (c.1291C>T) in the general population?

EPHB4 p.Arg431Ter (c.1291C>T) is very rare (popmax 0.0018%, amr) (gnomAD).

EPHB4 p.Arg431Ter

c.1291C>T · rs779782731 · VCV1458604

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0018%, amr)

Conditions

capillary malformation-arteriovenous malformation syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 17
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP -1, phastCons 1
Overall
CADD	40.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0018% Admixed American · 1/55,624 alleles

Overall 0.000142% 2/1,406,268 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0018%	55,624
European (non-Finnish)	8.72e-05%	1,146,378

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.Arg431Ter
Coding: c.1291C>T
MANE Select: NM_004444
dbSNP: rs779782731
Type: single nucleotide variant
Location: chr7:100819563 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 431: 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

capillary malformation-arteriovenous malformation syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPHB4 p.Arg431Gln Uncertain significance ★ ⚠ same residue
EPHB4 p.Gln41Ter Pathogenic ★ same condition
EPHB4 p.Val809fs Pathogenic ★ same condition
EPHB4 c.1691+1G>A Pathogenic/Likely pathogenic ★★ same type
EPHB4 c.2484+1G>A Pathogenic/Likely pathogenic ★★ same type
EPHB4 p.Arg269Ter Pathogenic/Likely pathogenic ★★ same type
EPHB4 p.Arg365Ter Pathogenic/Likely pathogenic ★★ same type
EPHB4 p.Arg394Ter Pathogenic ★★ same type

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-arg431ter (accessed [today's date]).

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