Is ENG p.Leu194fs (c.580_596del) pathogenic?

ENG p.Leu194fs (c.580596del) is classified Pathogenic in ENG (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-02). Absent from gnomAD; Associated with hereditary hemorrhagic telangiectasia.

What condition is associated with ENG p.Leu194fs (c.580_596del)?

ENG p.Leu194fs (c.580_596del) is associated with hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Leu194fs (c.580_596del) in the general population?

ENG p.Leu194fs (c.580_596del) is absent from gnomAD (gnomAD).

How is Hereditary hemorrhagic telangiectasia inherited?

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

ENG p.Leu194fs

c.580_596del · rs2131889284 · VCV1353949

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

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 5 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.9	GERP -3.6

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ENG
Protein: p.Leu194fs
Coding: c.580_596del
MANE Select: NM_001114753
dbSNP: rs2131889284
Type: Deletion
Location: chr9:127825788 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 194: a β-strand; a disulfide bond; a UniProt-annotated variant site (in hht1); the 'required for interaction with gdf2' region; the 'or2' 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.Leu194= Likely benign ★★ same residue
ENG p.Leu194Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
ENG p.Leu194_Arg197del Likely pathogenic ★ 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-leu194fs (accessed [today's date]).

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