Is EPHB4 p.Pro983Leu (c.2948C>T) pathogenic?

EPHB4 p.Pro983Leu (c.2948C>T) is classified Uncertain significance in EPHB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-15). AlphaMissense: likely benign (0.0801); Ultra-rare (popmax 0.0333%, mid); Associated with EPHB4-related disorder.

What condition is associated with EPHB4 p.Pro983Leu (c.2948C>T)?

EPHB4 p.Pro983Leu (c.2948C>T) is associated with EPHB4-related disorder (ClinVar).

How common is EPHB4 p.Pro983Leu (c.2948C>T) in the general population?

EPHB4 p.Pro983Leu (c.2948C>T) is ultra-rare (popmax 0.0333%, mid) (gnomAD).

What do computational predictors say about EPHB4 p.Pro983Leu (c.2948C>T)?

AlphaMissense predicts likely benign (score 0.0801) — an in-silico prediction, not a clinical call.

EPHB4 p.Pro983Leu

c.2948C>T · rs768926072 · VCV1797991

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0801 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

EPHB4-related disorder

Computational evidence

Protein change
AlphaMissense	0.0801	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -6.98	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP -0.17, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 3,002 bp · p 0.042 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0333% Middle Eastern · 2/6,010 alleles

Filtering AF 0.00586% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00165% 26/1,575,464 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0333%	3,005
Remaining individualsnot grpmax-eligible	0.00328%	30,451
European (non-Finnish)	0.0019%	52,628

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.Pro983Leu
Coding: c.2948C>T
MANE Select: NM_004444
dbSNP: rs768926072
Type: single nucleotide variant
Location: chr7:100803477 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 983: the 'disordered' region; a UniProt-annotated variant site (in cmavm2)

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

Disease context

EPHB4-related disorder

Similar variants

EPHB4 p.Pro983= Benign/Likely benign ★★ same residue
EPHB4 p.Pro983Arg Likely benign ★★ ⚠ same residue
EPHB4 p.Pro983Ser Uncertain significance ★ ⚠ same residue
EPHB4 c.1691+1G>A Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Arg269Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Arg785Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Gln537Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Leu494Pro 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-pro983leu (accessed [today's date]).

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