Is ENG p.Ile359Ser (c.1076T>G) pathogenic?

ENG p.Ile359Ser (c.1076T>G) is classified Uncertain significance in ENG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-28). AlphaMissense: likely pathogenic (0.8894); Absent from gnomAD v4.1; Associated with hereditary hemorrhagic telangiectasia.

What condition is associated with ENG p.Ile359Ser (c.1076T>G)?

ENG p.Ile359Ser (c.1076T>G) is associated with hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Ile359Ser (c.1076T>G) in the general population?

ENG p.Ile359Ser (c.1076T>G) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary hemorrhagic telangiectasia inherited?

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

What do computational predictors say about ENG p.Ile359Ser (c.1076T>G)?

AlphaMissense predicts likely pathogenic (score 0.8894) — an in-silico prediction, not a clinical call.

ENG p.Ile359Ser

c.1076T>G · rs2131885879 · VCV2683066

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8894 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary hemorrhagic telangiectasia

Computational evidence

Protein change
AlphaMissense	0.8894	likely pathogenic · top 7% in ENG
REVEL	0.184	benign-leaning
SaProt	LLR -12.69	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ENG
Protein: p.Ile359Ser
Coding: c.1076T>G
MANE Select: NM_001114753
dbSNP: rs2131885879
Type: single nucleotide variant
Location: chr9:127824362 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 359: a disulfide bond

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.Ile359Thr Uncertain significance ★★ ⚠ same residue
ENG p.Ile359= Likely benign ★★ same residue
ENG p.Ile359Asn Uncertain significance ★ ⚠ 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
ENG p.Gly331Ser 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-ile359ser (accessed [today's date]).

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