Is ENG p.Val483Ile (c.1447G>A) pathogenic?

ENG p.Val483Ile (c.1447G>A) is classified Likely benign in ENG (ClinVar, Expert panel, 5 submitters; last evaluated 2025-02-04). AlphaMissense: likely benign (0.0677); Ultra-rare (popmax 0.0866%, afr); Associated with telangiectasia, hereditary hemorrhagic, type 1.

What condition is associated with ENG p.Val483Ile (c.1447G>A)?

ENG p.Val483Ile (c.1447G>A) is associated with telangiectasia, hereditary hemorrhagic, type 1, hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Val483Ile (c.1447G>A) in the general population?

ENG p.Val483Ile (c.1447G>A) is ultra-rare (popmax 0.0866%, afr) (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.Val483Ile (c.1447G>A)?

AlphaMissense predicts likely benign (score 0.0677) — an in-silico prediction, not a clinical call.

ENG p.Val483Ile

c.1447G>A · rs141330288 · VCV414304

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0677 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0866%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

telangiectasia, hereditary hemorrhagic, type 1

ClinGen expert panel — Hereditary Hemorrhagic Telangiectasia VCEP

Likely Benign for telangiectasia, hereditary hemorrhagic, type 1. Applied ACMG criteria (verbatim):

BP4 BS1_Supporting

Curation rationale (ClinGen, verbatim)

The NM_001114753.3: c.1447G>A variant in ENG is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 483 (p.Val483Ile). The filtering allele frequency (the lower threshold of the 95% CI of 28/19926) of the c.1447G>A variant in ENG is 0.0009914 for East Asian chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.0008-0.002) for BS1_Supporting, and therefore meets this criterion (BS1_Supporting). The computational predictor REVEL gives a score of 0.094, which is below the threshold of ≤0.15, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on ENG function (BP4). In summary, this variant meets the criteria to be classified as likely benign 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: BS1_Supporting, BP4 (specifications version 1.1.0; 02/04/2025).

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

Computational evidence

Protein change
AlphaMissense	0.0677	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -3.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.9	GERP -2.8
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	1.647	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

Grpmax group 0.0866% African / African-American · 65/75,050 alleles

Filtering AF 0.0697% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0635%

Overall 0.00806% 130/1,613,772 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0866%	1,155
East Asian	0.0691%	1,448
Remaining individualsnot grpmax-eligible	0.0112%	8,929
Admixed American	0.00833%	12,005
South Asian	0.00329%	30,362
European (non-Finnish)	0.00161%	62,106

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.Val483Ile
Coding: c.1447G>A
MANE Select: NM_001114753
dbSNP: rs141330288
Type: single nucleotide variant
Location: chr9:127818359 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 483: the zp domain

Full ENG gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

telangiectasia, hereditary hemorrhagic, type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary hemorrhagic telangiectasia

For Hereditary hemorrhagic telangiectasia (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

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
ENG p.Gly603Arg Likely pathogenic ★★★ same condition
ENG p.Leu221Pro Likely pathogenic ★★★ same condition
ENG p.Leu506His 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-val483ile (accessed [today's date]).

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