Is EPHB4 p.Thr526Ala (c.1576A>G) pathogenic?

EPHB4 p.Thr526Ala (c.1576A>G) is classified Conflicting classifications of pathogenicity in EPHB4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-15). AlphaMissense: likely pathogenic (0.6946); Very rare (popmax 0.00738%, amr); Associated with lymphatic malformation 7.

What condition is associated with EPHB4 p.Thr526Ala (c.1576A>G)?

EPHB4 p.Thr526Ala (c.1576A>G) is associated with lymphatic malformation 7, capillary malformation-arteriovenous malformation 2 (ClinVar).

How common is EPHB4 p.Thr526Ala (c.1576A>G) in the general population?

EPHB4 p.Thr526Ala (c.1576A>G) is very rare (popmax 0.00738%, amr) (gnomAD).

What do computational predictors say about EPHB4 p.Thr526Ala (c.1576A>G)?

AlphaMissense predicts likely pathogenic (score 0.6946) — an in-silico prediction, not a clinical call.

EPHB4 p.Thr526Ala

c.1576A>G · rs771353399 · VCV1399139

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6946 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00738%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

lymphatic malformation 7

Computational evidence

Protein change
AlphaMissense	0.6946	likely pathogenic
REVEL	0.406	indeterminate
SaProt	LLR -12.09	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.3, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	26.0	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 0.00738% Admixed American · 4/54,182 alleles

Filtering AF 0.00242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00146%

Overall 0.000282% 4/1,418,746 alleles · very rare

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.Thr526Ala
Coding: c.1576A>G
MANE Select: NM_004444
dbSNP: rs771353399
Type: single nucleotide variant
Location: chr7:100817204 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 526: a UniProt-annotated variant site (in cmavm2); the fibronectin type-iii 2 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.Thr526Ile Uncertain significance ★ ⚠ same residue
EPHB4 c.2484+1G>A Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Arg365Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Arg739Gln 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

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-thr526ala (accessed [today's date]).

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