Is ENG p.Pro528fs (c.1583del) pathogenic?

ENG p.Pro528fs (c.1583del) is classified Pathogenic in ENG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-24). Ultra-rare (gnomAD MAF 7.135e-07); Associated with hereditary hemorrhagic telangiectasia.

What condition is associated with ENG p.Pro528fs (c.1583del)?

ENG p.Pro528fs (c.1583del) is associated with hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Pro528fs (c.1583del) in the general population?

ENG p.Pro528fs (c.1583del) is ultra-rare (gnomAD MAF 7.135e-07) (gnomAD).

How is Hereditary hemorrhagic telangiectasia inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

ENG p.Pro528fs

c.1583del · rs1554809253 · VCV523407

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (gnomAD MAF 7.135e-07)

Conditions

hereditary hemorrhagic telangiectasia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 12 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2.4	GERP -1.9

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

Global frequency 7.13e-05% via dbSNP · ultra-rare

No ancestry breakdown or filtering allele frequency is available for this variant, so BA1/BS1 cannot be assessed from this figure alone.

Variant & gene context

Gene: ENG
Protein: p.Pro528fs
Coding: c.1583del
MANE Select: NM_001114753
dbSNP: rs1554809253
Type: Deletion
Location: chr9:127818223 (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

hereditary hemorrhagic telangiectasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary hemorrhagic telangiectasia (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ENG p.Pro528= Likely benign ★★ same residue
ENG p.Pro528Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
ENG p.Pro528Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
ENG c.1687delG Pathogenic ★★ same condition
ENG p.Ala55fs Pathogenic ★★ same condition
ENG p.Arg232_Thr233del Likely pathogenic ★★ same condition
ENG p.Arg399fs Pathogenic/Likely pathogenic ★★ same condition
ENG p.Asn163fs Pathogenic/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-pro528fs (accessed [today's date]).

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