Is ENG p.Asn307Ile (c.920A>T) pathogenic?

ENG p.Asn307Ile (c.920A>T) is classified Conflicting classifications of pathogenicity in ENG (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-05-29). AlphaMissense: likely pathogenic (0.8761); Absent from gnomAD v4.1; Associated with hereditary hemorrhagic telangiectasia.

What condition is associated with ENG p.Asn307Ile (c.920A>T)?

ENG p.Asn307Ile (c.920A>T) is associated with hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Asn307Ile (c.920A>T) in the general population?

ENG p.Asn307Ile (c.920A>T) 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.Asn307Ile (c.920A>T)?

AlphaMissense predicts likely pathogenic (score 0.8761) — an in-silico prediction, not a clinical call.

ENG p.Asn307Ile

c.920A>T · rs779815395 · VCV1766194

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8761 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary hemorrhagic telangiectasia

ClinGen expert panel — Hereditary Hemorrhagic Telangiectasia VCEP

Uncertain Significance for telangiectasia, hereditary hemorrhagic, type 1. Applied ACMG criteria (verbatim):

PM2_Supporting PS4_Supporting

Curation rationale (ClinGen, verbatim)

The NM_001114753.3: c.920A>T variant in ENG is a missense variant predicted to cause substitution of asparagine by isoleucine at amino acid 307 (p.Asn307Ile). This variant has not been observed in gnomAD v2.1 (PM2_Supporting) but has been observed in one individual with suspected HHT (PS4_Supporting). The computational predictor REVEL gives a score of 0.303, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM2_Supporting, PS4_Supporting (specifications version 1.1.0; 02/13/2026).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.8761	likely pathogenic · top 7% in ENG
REVEL	0.303	indeterminate
SaProt	LLR -12.34	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	24.1	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.Asn307Ile
Coding: c.920A>T
MANE Select: NM_001114753
dbSNP: rs779815395
Type: single nucleotide variant
Location: chr9:127824871 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 307: 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.Asn307Asp Uncertain significance ★★ ⚠ same residue
ENG p.Asn307= Likely benign ★ same residue
ENG p.Asn307Ser Likely benign ★ 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-asn307ile (accessed [today's date]).

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