Is ENG p.Ser328fs (c.981del) pathogenic?

ENG p.Ser328fs (c.981del) is classified Pathogenic in ENG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-27). Very rare (popmax 0.00187%, amr); Associated with hereditary hemorrhagic telangiectasia.

What condition is associated with ENG p.Ser328fs (c.981del)?

ENG p.Ser328fs (c.981del) is associated with hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Ser328fs (c.981del) in the general population?

ENG p.Ser328fs (c.981del) is very rare (popmax 0.00187%, amr) (gnomAD).

How is Hereditary hemorrhagic telangiectasia inherited?

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

ENG p.Ser328fs

c.981del · VCV4722179

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00187%, amr)

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 7 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.4	GERP -3, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00187% Admixed American · 1/53,384 alleles

Overall 7.07e-05% 1/1,414,858 alleles · very rare

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.Ser328fs
Coding: c.981del
MANE Select: NM_001114753
Type: Deletion
Location: chr9:127824810 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 328: a disulfide bond; the 'required for interaction with gdf2' region; the 'or1, c-terminal part' region

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.Ser328Ter Pathogenic ★★ same residue
ENG p.Ser328Thr Uncertain significance ★ ⚠ 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
ENG p.Asn423fs 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-ser328fs (accessed [today's date]).

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