Is EPHB4 p.Pro983= (c.2949G>A) pathogenic?

EPHB4 p.Pro983= (c.2949G>A) is classified Benign/Likely benign in EPHB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-02). Rare (popmax 0.591%, eas); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Pro983= (c.2949G>A)?

EPHB4 p.Pro983= (c.2949G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Pro983= (c.2949G>A) in the general population?

EPHB4 p.Pro983= (c.2949G>A) is rare (popmax 0.591%, eas) (gnomAD).

EPHB4 p.Pro983=

c.2949G>A · rs112803997 · VCV1798004

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.591%, eas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.68	GERP -2.3, phastCons 0.86
Overall
CADD	5.221	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.591% East Asian · 258/43,676 alleles

Filtering AF 0.532% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.509%

Overall 0.0194% 306/1,575,378 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.591%	169
Remaining individualsnot grpmax-eligible	0.00656%	15,236
European (non-Finnish)	0.00354%	28,237
Admixed American	0.00183%	54,516
African / African-American	0.00134%	74,648
South Asian	0.00116%	86,132

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.Pro983=
Coding: c.2949G>A
MANE Select: NM_004444
dbSNP: rs112803997
Type: single nucleotide variant
Location: chr7:100803476 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPHB4 p.Pro983Arg Likely benign ★★ ⚠ same residue
EPHB4 p.Pro983Ser Uncertain significance ★ ⚠ same residue
EPHB4 p.Pro983Leu Uncertain significance ★★ ⚠ same residue
EPHB4 c.1870+5G>C Uncertain significance ★★ same condition
EPHB4 p.Ala262Val Uncertain significance ★★ ⚠ same condition
EPHB4 p.Ala345Gly Uncertain significance ★★ ⚠ same condition
EPHB4 p.Ala931Thr Uncertain significance ★★ ⚠ same condition
EPHB4 p.Arg148Trp 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-pro983 (accessed [today's date]).

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