Is EPHB4 p.Leu73Arg (c.218T>G) pathogenic?

EPHB4 p.Leu73Arg (c.218T>G) is classified Uncertain significance in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-21). AlphaMissense: likely pathogenic (0.9901); Absent from gnomAD v4.1.

How common is EPHB4 p.Leu73Arg (c.218T>G) in the general population?

EPHB4 p.Leu73Arg (c.218T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EPHB4 p.Leu73Arg (c.218T>G)?

AlphaMissense predicts likely pathogenic (score 0.9901) — an in-silico prediction, not a clinical call.

EPHB4 p.Leu73Arg

c.218T>G · rs2485049729 · VCV2764012

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9901 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9901	likely pathogenic
REVEL	0.523	indeterminate
SaProt	LLR -13.51	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 2.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	26.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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.Leu73Arg
Coding: c.218T>G
MANE Select: NM_004444
dbSNP: rs2485049729
Type: single nucleotide variant
Location: chr7:100823837 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 73: a disulfide bond; the eph lbd domain; a β-strand

Full EPHB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPHB4 c.1691+1G>A Pathogenic/Likely pathogenic ★★ same type
EPHB4 c.2484+1G>A Pathogenic/Likely pathogenic ★★ same type
EPHB4 p.Arg269Ter Pathogenic/Likely pathogenic ★★ same type
EPHB4 p.Arg365Ter Pathogenic/Likely pathogenic ★★ same type
EPHB4 p.Arg394Ter Pathogenic ★★ same type
EPHB4 p.Arg431Ter Pathogenic ★★ same type
EPHB4 p.Arg739Gln Pathogenic ★★ same type
EPHB4 p.Arg739Ter Pathogenic ★★ same type

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-leu73arg (accessed [today's date]).

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