Is ENG p.Ile263= (c.789C>T) pathogenic?

ENG p.Ile263= (c.789C>T) is classified Likely benign in ENG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-28). Very rare (popmax 0.00446%, eas); Associated with Cardiovascular phenotype.

What condition is associated with ENG p.Ile263= (c.789C>T)?

ENG p.Ile263= (c.789C>T) is associated with Cardiovascular phenotype, hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Ile263= (c.789C>T) in the general population?

ENG p.Ile263= (c.789C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

ENG p.Ile263=

c.789C>T · rs1248553739 · VCV2892120

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.12	GERP -0.68, phastCons 0.69
Overall
CADD	13.64	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,804 alleles

Filtering AF 0.00074% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000186% 3/1,612,512 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,402
South Asian	0.0011%	91,000

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.Ile263=
Coding: c.789C>T
MANE Select: NM_001114753
dbSNP: rs1248553739
Type: single nucleotide variant
Location: chr9:127825258 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 263: a β-strand; a disulfide bond; a UniProt-annotated variant site (in hht1); 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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary hemorrhagic telangiectasia

Similar variants

ENG p.Ile263del Pathogenic/Likely pathogenic ★★ same residue
ENG p.Ile263Ser Likely pathogenic ★ same residue
ENG p.Ile263Asn 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-ile263 (accessed [today's date]).

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