Is EPHB4 p.Ile782Ser (c.2345T>G) pathogenic?

EPHB4 p.Ile782Ser (c.2345T>G) is classified Pathogenic in EPHB4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2018-12-19). AlphaMissense: likely pathogenic (0.9995); Absent from gnomAD v4.1; Associated with lymphatic malformation 7.

What condition is associated with EPHB4 p.Ile782Ser (c.2345T>G)?

EPHB4 p.Ile782Ser (c.2345T>G) is associated with lymphatic malformation 7 (ClinVar).

How common is EPHB4 p.Ile782Ser (c.2345T>G) in the general population?

EPHB4 p.Ile782Ser (c.2345T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EPHB4 p.Ile782Ser (c.2345T>G)?

AlphaMissense predicts likely pathogenic (score 0.9995) — an in-silico prediction, not a clinical call.

EPHB4 p.Ile782Ser

c.2345T>G · rs1057519264 · VCV374837

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9995 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

lymphatic malformation 7

Computational evidence

Protein change
AlphaMissense	0.9995	likely pathogenic ✓ concordant with ClinVar · top 2% in EPHB4
REVEL	0.64	indeterminate
SaProt	LLR -14.76	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 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 6,734 bp · p 5.4e-12 · regional, not allelic
Overall
CADD	32.0	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

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.Ile782Ser
Coding: c.2345T>G
MANE Select: NM_004444
dbSNP: rs1057519264
Type: single nucleotide variant
Location: chr7:100806559 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 782: a UniProt-annotated variant site (in cmavm2); a UniProt-annotated variant site (in lmphm7; loss of kinase activity); the protein kinase 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

Similar variants

EPHB4 p.Ile782= Likely benign ★ same residue
EPHB4 p.Arg365Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Arg739Gln Pathogenic ★★ same condition
EPHB4 p.Gln580Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Ser280Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Lys859Arg Uncertain significance ★★ ⚠ same condition
EPHB4 p.Met728Val Uncertain significance ★★ ⚠ same condition
EPHB4 p.Ser299Leu Uncertain significance ★★ ⚠ 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-ile782ser (accessed [today's date]).

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