Is EPHB4 p.Arg838Trp (c.2512C>T) pathogenic?

EPHB4 p.Arg838Trp (c.2512C>T) is classified Conflicting classifications of pathogenicity in EPHB4 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-04-04). AlphaMissense: likely pathogenic (0.996); Very rare (popmax 0.00233%, eas); Associated with capillary malformation-arteriovenous malformation 2.

What condition is associated with EPHB4 p.Arg838Trp (c.2512C>T)?

EPHB4 p.Arg838Trp (c.2512C>T) is associated with capillary malformation-arteriovenous malformation 2 (ClinVar).

How common is EPHB4 p.Arg838Trp (c.2512C>T) in the general population?

EPHB4 p.Arg838Trp (c.2512C>T) is very rare (popmax 0.00233%, eas) (gnomAD).

What do computational predictors say about EPHB4 p.Arg838Trp (c.2512C>T)?

AlphaMissense predicts likely pathogenic (score 0.996) — an in-silico prediction, not a clinical call.

EPHB4 p.Arg838Trp

c.2512C>T · rs764827256 · VCV691550

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.996 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00233%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

capillary malformation-arteriovenous malformation 2

Computational evidence

Protein change
AlphaMissense	0.996	likely pathogenic
REVEL	0.898	moderately pathogenic-leaning
SaProt	LLR -15.13	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 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 3,002 bp · p 0.042 · 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 0.00233% East Asian · 1/42,836 alleles

Filtering AF 8.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.5e-05%

Overall 0.000327% 5/1,526,982 alleles · very rare exomes 4/1,374,834 · genomes 1/152,148 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00233%	42,836
European (non-Finnish)	0.000351%	284,880

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.Arg838Trp
Coding: c.2512C>T
MANE Select: NM_004444
dbSNP: rs764827256
Type: single nucleotide variant
Location: chr7:100805667 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 838: a UniProt-annotated variant site (in cmavm2); a UniProt-annotated variant site (in cmavm2; the mutant protein is not detected by western blot; loss of localization to cell membrane); the protein kinase domain

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

Disease context

capillary malformation-arteriovenous malformation 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPHB4 p.Arg838Gly Likely pathogenic ★ 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-arg838trp (accessed [today's date]).

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