ACVRL1 p.Pro459=
c.1377G>A · rs61734312 · VCV1035031
Uncertain significance
Multiple submitters
Classification
Uncertain significance
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
very rare (popmax 0.00329%, sas)
Conditions
2
Cardiovascular phenotype
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.24 | donor loss · deltas |
|---|---|---|
| Pangolin | Δ0.34 | loss · gain 0.01 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP 6.3 | GERP 1.5, phastCons 1 |
| Overall | ||
| CADD | 21.4 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00329%
South Asian · 3/91,088 alleles
Filtering AF
0.000875%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000474%
Overall
0.00105%
17/1,614,004 alleles · very rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.00329% | 30,363 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,482 |
| European (non-Finnish) | 0.0011% | 90,770 |
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
- ACVRL1
- Protein
- p.Pro459=
- Coding
- c.1377G>A
- MANE Select
- NM_000020
- dbSNP
- rs61734312
- Type
- single nucleotide variant
- Location
- chr12:51919115 (GRCh38)
- Gene constraint
- LOEUF 0.57 · pLI 0.51 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 82.77 · 7 PDB
- Residue 459
- a β-strand; the protein kinase domain
Similar variants
- ACVRL1 p.Pro459Leu Uncertain significance ★★ ⚠ same residue
- ACVRL1 p.Pro459fs Likely pathogenic ★ same residue
- ACVRL1 p.Arg411Gln Pathogenic ★★★ same condition
- ACVRL1 p.Asn98Ser Likely pathogenic ★★★ ⚠ same condition
- ACVRL1 p.Cys46Ser Likely pathogenic ★★★ same condition
- ACVRL1 p.Cys51Gly Likely pathogenic ★★★ same condition
- ACVRL1 p.Cys89Phe Likely pathogenic ★★★ same condition
- ACVRL1 p.Gln490Ter 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/acvrl1-p-pro459 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown