Is EPHB4 p.Leu347fs (c.1039dup) pathogenic?

EPHB4 p.Leu347fs (c.1039dup) is classified Pathogenic in EPHB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-11-21). Very rare (popmax 0.00136%, afr); Associated with lymphatic malformation 7.

What condition is associated with EPHB4 p.Leu347fs (c.1039dup)?

EPHB4 p.Leu347fs (c.1039dup) is associated with lymphatic malformation 7, capillary malformation-arteriovenous malformation 2 (ClinVar).

How common is EPHB4 p.Leu347fs (c.1039dup) in the general population?

EPHB4 p.Leu347fs (c.1039dup) is very rare (popmax 0.00136%, afr) (gnomAD).

EPHB4 p.Leu347fs

c.1039dup · rs767827881 · VCV1426188

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00136%, afr)

Conditions

lymphatic malformation 7

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP -2.3, phastCons 1
Overall
CADD	33.0	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 0.00136% African / African-American · 1/73,492 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00032% 5/1,561,220 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00136%	73,492
South Asian	0.00117%	85,798
European (non-Finnish)	0.00026%	384,398

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.Leu347fs
Coding: c.1039dup
MANE Select: NM_004444
dbSNP: rs767827881
Type: Duplication
Location: chr7:100819814 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 347: 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

lymphatic malformation 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: capillary malformation-arteriovenous malformation 2

Similar variants

EPHB4 p.Leu347= Likely benign ★★ same residue
EPHB4 c.2484+2dup Likely pathogenic ★ same condition
EPHB4 p.Asp376fs Likely pathogenic ★ same condition
EPHB4 p.Asp385fs Likely pathogenic ★ same condition
EPHB4 p.Asp758fs Likely pathogenic ★ same condition
EPHB4 p.Glu388fs Likely pathogenic ★ same condition
EPHB4 p.Gly622fs Likely pathogenic ★ same condition
EPHB4 p.Leu12fs 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-leu347fs (accessed [today's date]).

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