Is EPHB4 p.Trp72Ter (c.216G>A) pathogenic?

EPHB4 p.Trp72Ter (c.216G>A) is classified Pathogenic/Likely pathogenic in EPHB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-05-06). Absent from gnomAD v4.1; Associated with EPHB4-related disorder.

What condition is associated with EPHB4 p.Trp72Ter (c.216G>A)?

EPHB4 p.Trp72Ter (c.216G>A) is associated with EPHB4-related disorder, capillary malformation-arteriovenous malformation 2 (ClinVar).

How common is EPHB4 p.Trp72Ter (c.216G>A) in the general population?

EPHB4 p.Trp72Ter (c.216G>A) is absent from gnomAD v4.1 (gnomAD).

EPHB4 p.Trp72Ter

c.216G>A · rs2485049740 · VCV1806264

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 3 of 17
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Overall
CADD	39.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EPHB4
Protein: p.Trp72Ter
Coding: c.216G>A
MANE Select: NM_004444
dbSNP: rs2485049740
Type: single nucleotide variant
Location: chr7:100823839 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 72: the eph lbd domain; a β-strand

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.Trp72Cys 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-trp72ter (accessed [today's date]).

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