Is ENG p.Val133Ile (c.396_397delinsAA) pathogenic?

ENG p.Val133Ile (c.396397delinsAA) is classified Uncertain significance in ENG (ClinVar, Single submitter, 1 submitter; last evaluated 2017-03-26). Absent from gnomAD; Associated with hereditary hemorrhagic telangiectasia.

What condition is associated with ENG p.Val133Ile (c.396_397delinsAA)?

ENG p.Val133Ile (c.396_397delinsAA) is associated with hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Val133Ile (c.396_397delinsAA) in the general population?

ENG p.Val133Ile (c.396_397delinsAA) 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.Val133Ile

c.396_397delinsAA · rs1554810507 · VCV458348

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

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.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1	GERP -1.3
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic

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.Val133Ile
Coding: c.396_397delinsAA
MANE Select: NM_001114753
dbSNP: rs1554810507
Type: Indel
Location: chr9:127826636 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 133: a β-strand; a disulfide bond; 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.Val133fs Pathogenic ★★ same residue
ENG p.Val133Phe Uncertain significance ★ ⚠ same residue
ENG p.Lys374Ser Pathogenic/Likely pathogenic ★★ same condition
ENG p.Ser328Ter Pathogenic ★★ same condition
ENG p.Thr344fs Pathogenic ★★ same condition
ENG p.Ala60Glu Benign/Likely benign ★★ same condition
ENG c.1135-3_1135-2delinsAG Likely pathogenic ★ same condition
ENG p.Lys291fs 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-val133ile (accessed [today's date]).

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