Is ENG p.Pro528= (c.1584G>A) pathogenic?

ENG p.Pro528= (c.1584G>A) is classified Likely benign in ENG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-03). Ultra-rare (popmax 0.0187%, sas); Associated with Cardiovascular phenotype.

What condition is associated with ENG p.Pro528= (c.1584G>A)?

ENG p.Pro528= (c.1584G>A) is associated with Cardiovascular phenotype, hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Pro528= (c.1584G>A) in the general population?

ENG p.Pro528= (c.1584G>A) is ultra-rare (popmax 0.0187%, sas) (gnomAD).

ENG p.Pro528=

c.1584G>A · rs189572386 · VCV1156862

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, sas)

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 -2.4	GERP -1.9
Overall
CADD	5.998	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% South Asian · 17/91,086 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00976%

Overall 0.00242% 39/1,614,142 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0187%	5,358
Admixed American	0.00333%	30,011
Remaining individualsnot grpmax-eligible	0.0032%	31,253
African / African-American	0.00267%	37,514
European (non-Finnish)	0.00136%	73,752

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: ENG
Protein: p.Pro528=
Coding: c.1584G>A
MANE Select: NM_001114753
dbSNP: rs189572386
Type: single nucleotide variant
Location: chr9:127818222 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 528: a disulfide bond; the zp domain

Full ENG 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

Also linked: hereditary hemorrhagic telangiectasia

Similar variants

ENG p.Pro528Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
ENG p.Pro528Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
ENG p.Pro528Ser Uncertain significance ★ ⚠ same residue
ENG p.Pro528fs Pathogenic ★★ same residue
ENG p.Arg529His Pathogenic ★★★ ⚠ same condition
ENG p.Asn423Ser Likely pathogenic ★★★ ⚠ same condition
ENG p.Cys382Tyr Pathogenic ★★★ same condition
ENG p.Cys549Gly 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/eng-p-pro528 (accessed [today's date]).

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