Is EPHB4 p.Arg352Ter (c.1054C>T) pathogenic?

EPHB4 p.Arg352Ter (c.1054C>T) is classified Conflicting classifications of pathogenicity in EPHB4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-01-26). Very rare (popmax 0.00407%, afr); Associated with EPHB4-related disorder.

What condition is associated with EPHB4 p.Arg352Ter (c.1054C>T)?

EPHB4 p.Arg352Ter (c.1054C>T) is associated with EPHB4-related disorder, capillary malformation-arteriovenous malformation 2 (ClinVar).

How common is EPHB4 p.Arg352Ter (c.1054C>T) in the general population?

EPHB4 p.Arg352Ter (c.1054C>T) is very rare (popmax 0.00407%, afr) (gnomAD).

EPHB4 p.Arg352Ter

c.1054C>T · rs898898802 · VCV1303898

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00407%, afr)

Conditions

EPHB4-related disorder

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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.3	GERP 0.14, phastCons 1
Overall
CADD	36.0	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 0.00407% African / African-American · 3/73,728 alleles

Filtering AF 0.00108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0005%

Overall 0.000319% 5/1,568,162 alleles · very rare exomes 1/1,415,954 · genomes 4/152,208 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00407%	24,576
South Asian	0.00116%	86,550
European (non-Finnish)	8.64e-05%	1,157,136

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.Arg352Ter
Coding: c.1054C>T
MANE Select: NM_004444
dbSNP: rs898898802
Type: single nucleotide variant
Location: chr7:100819800 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 352: 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

EPHB4-related disorder

Also linked: capillary malformation-arteriovenous malformation 2

Similar variants

EPHB4 p.Arg352Leu Uncertain significance ★ ⚠ same residue
EPHB4 c.1691+1G>A Pathogenic/Likely pathogenic ★★ same condition
EPHB4 c.2484+1G>A Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Arg269Ter 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.Arg785Ter 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-arg352ter (accessed [today's date]).

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