ClinGen expert panel — Hereditary Hemorrhagic Telangiectasia VCEP
Uncertain Significance for telangiectasia, hereditary hemorrhagic, type 1. Applied ACMG criteria (verbatim):
PM2_Supporting BP4
Curation rationale (ClinGen, verbatim)
The NM_001114753.3: c.1961C>G variant in ENG is a missense variant predicted to cause substitution of threonine by serine at amino acid 654 (p.Thr654Ser). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.126, 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). Due to limited evidence, this variant is 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, BP4 (specification version 1.0.0; 1/4/2024).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.3547 | ambiguous |
|---|---|---|
| REVEL | 0.126 | moderately benign-leaning |
| SaProt | LLR -5.38 | tolerated |
| ⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 0.96, phastCons 1 |
| Regional constraint | o/e 0.86 | unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic |
| Overall | ||
| CADD | 27.0 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
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.Thr654Ser
- Coding
- c.1961C>G
- MANE Select
- NM_001114753
- dbSNP
- rs1050077
- Type
- single nucleotide variant
- Location
- chr9:127815698 (GRCh38)
- Gene constraint
- LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 80.84 · 3 PDB
- Residue 654
- the 'disordered' region
Disease context
telangiectasia, hereditary hemorrhagic, type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsFor Hereditary hemorrhagic telangiectasia (Orphanet):
- Inheritance
- Autosomal dominant
- Onset
- All ages
- Prevalence
- 1-5 / 10 000 (Europe)
Similar variants
- ENG p.Thr654= 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
- ENG p.Gly603Arg Likely pathogenic ★★★ same condition
- ENG p.Leu221Pro 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-thr654ser (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown