Is EPHB4 p.Leu874Pro (c.2621T>C) pathogenic?

EPHB4 p.Leu874Pro (c.2621T>C) is classified Conflicting classifications of pathogenicity in EPHB4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2022-12-27). AlphaMissense: likely pathogenic (0.9997); Absent from gnomAD v4.1; Associated with EPHB4-related disorder.

What condition is associated with EPHB4 p.Leu874Pro (c.2621T>C)?

EPHB4 p.Leu874Pro (c.2621T>C) is associated with EPHB4-related disorder, capillary malformation-arteriovenous malformation 2 (ClinVar).

How common is EPHB4 p.Leu874Pro (c.2621T>C) in the general population?

EPHB4 p.Leu874Pro (c.2621T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EPHB4 p.Leu874Pro (c.2621T>C)?

AlphaMissense predicts likely pathogenic (score 0.9997) — an in-silico prediction, not a clinical call.

EPHB4 p.Leu874Pro

c.2621T>C · rs1584652900 · VCV691542

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9997 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,538,460)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

EPHB4-related disorder

Computational evidence

Protein change
AlphaMissense	0.9997	likely pathogenic · top 2% in EPHB4
REVEL	0.936	strongly pathogenic-leaning
SaProt	LLR -16.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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 0.87	unconstrained · MANE · 3,002 bp · p 0.042 · 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

No allele count reported in gnomAD v4.1 (AN 1,538,460). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: EPHB4
Protein: p.Leu874Pro
Coding: c.2621T>C
MANE Select: NM_004444
dbSNP: rs1584652900
Type: single nucleotide variant
Location: chr7:100805558 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 874: an α-helix; a UniProt-annotated variant site (in cmavm2); a UniProt-annotated variant site (in cmavm2; uncertain significance); the protein kinase 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.Leu874Val Uncertain significance ★ ⚠ same residue
EPHB4 p.Leu874= Likely benign ★ 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

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-leu874pro (accessed [today's date]).

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