Is EPHB4 p.Pro327Leu (c.980C>T) pathogenic?

EPHB4 p.Pro327Leu (c.980C>T) is classified Uncertain significance in EPHB4 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-08-07). AlphaMissense: likely pathogenic (0.9688); Very rare (popmax 0.000175%, nfe); Associated with tetralogy of fallot.

What condition is associated with EPHB4 p.Pro327Leu (c.980C>T)?

EPHB4 p.Pro327Leu (c.980C>T) is associated with tetralogy of fallot (ClinVar).

How common is EPHB4 p.Pro327Leu (c.980C>T) in the general population?

EPHB4 p.Pro327Leu (c.980C>T) is very rare (popmax 0.000175%, nfe) (gnomAD).

What do computational predictors say about EPHB4 p.Pro327Leu (c.980C>T)?

AlphaMissense predicts likely pathogenic (score 0.9688) — an in-silico prediction, not a clinical call.

EPHB4 p.Pro327Leu

c.980C>T · rs1057515420 · VCV222000

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9688 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000175%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tetralogy of fallot

Computational evidence

Protein change
AlphaMissense	0.9688	likely pathogenic
REVEL	0.729	pathogenic-leaning
SaProt	LLR -14.74	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 9.8	GERP 2.5, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	31.0	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

Grpmax group 0.000175% European (non-Finnish) · 2/1,143,224 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000129% 2/1,545,386 alleles · very rare exomes 2/1,393,024 · genomes 0/152,362 · joint denominator

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.Pro327Leu
Coding: c.980C>T
MANE Select: NM_004444
dbSNP: rs1057515420
Type: single nucleotide variant
Location: chr7:100819874 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 327: 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

tetralogy of fallot — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPHB4 p.Pro327= Likely benign ★★ same residue
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

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-pro327leu (accessed [today's date]).

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