ENG p.Val588Ile
c.1762G>A · rs201768056 · VCV237024
ClinGen expert panel — Hereditary Hemorrhagic Telangiectasia VCEP
Likely Benign for telangiectasia, hereditary hemorrhagic, type 1. Applied ACMG criteria (verbatim):
BP5 BP4
Curation rationale (ClinGen, verbatim)
The NM_001114753.3: c.1762G>A variant in ENG is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 588 (p.Val588Ile). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0003436 (43/125140 alleles) in the non-Finnish European population. The computational predictor REVEL gives a score of 0.043, which is below the threshold of ≤0.1, 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). This variant has been observed in a patient with an alternate molecular basis for disease (pathogenic variant identified in ACVRL1) (BP5; internal lab contributors). 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: BP4, BP5 (specifications version 1.1.0; 09/11/2024).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.1011 | likely benign |
|---|---|---|
| REVEL | 0.043 | moderately benign-leaning |
| SaProt | LLR -6.42 | 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 0.65 | GERP -3.3, phastCons 0.12 |
| Regional constraint | o/e 0.86 | unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic |
| Overall | ||
| CADD | 13.36 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Ashkenazi Jewishnot grpmax-eligible | 0.0339% | 2,951 |
| Finnishnot grpmax-eligible | 0.0254% | 3,935 |
| European (non-Finnish)grpmax | 0.0164% | 6,110 |
| Remaining individualsnot grpmax-eligible | 0.0128% | 7,785 |
| African / African-American | 0.00267% | 37,446 |
| East Asian | 0.00223% | 44,808 |
| Admixed American | 0.00168% | 59,648 |
Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.
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.Val588Ile
- Coding
- c.1762G>A
- MANE Select
- NM_001114753
- dbSNP
- rs201768056
- Type
- single nucleotide variant
- Location
- chr9:127816033 (GRCh38)
- Gene constraint
- LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 80.84 · 3 PDB
Disease context
telangiectasia, hereditary hemorrhagic, type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso 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-val588ile (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown