HCN4 p.Pro161=
c.483C>G · rs1595837408 · VCV1743471
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
very rare (popmax 9.48e-05%, nfe)
Conditions
2
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 0.5 | GERP -2.2, phastCons 0.099 |
| Overall | ||
| CADD | 7.446 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
9.48e-05%
European (non-Finnish) · 1/1,054,568 alleles
Overall
7.47e-05%
1/1,338,868 alleles · very rare
exomes 1/1,187,752 · genomes 0/151,116 · joint denominator
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
- HCN4
- Protein
- p.Pro161=
- Coding
- c.483C>G
- MANE Select
- NM_005477
- dbSNP
- rs1595837408
- Type
- single nucleotide variant
- Location
- chr15:73367788 (GRCh38)
- Gene constraint
- LOEUF 0.571 · pLI 0.15 (gnomAD)
- Structure
- AlphaFold pLDDT 61.86 · 8 PDB
- Residue 161
- the 'disordered' region
Similar variants
- HCN4 p.Pro161Ser Uncertain significance ★★ ⚠ same residue
- HCN4 p.Pro161Thr Uncertain significance ★★ ⚠ same residue
- HCN4 c.2143+1G>A Likely pathogenic ★★ same condition
- HCN4 p.Ala485Val Pathogenic/Likely pathogenic ★★ same condition
- HCN4 p.Arg375Cys Pathogenic/Likely pathogenic ★★ same condition
- HCN4 p.Gly480Ser Pathogenic/Likely pathogenic ★★ same condition
- HCN4 p.Gly480Val Likely pathogenic ★★ same condition
- HCN4 p.Gly482Arg Pathogenic/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/hcn4-p-pro161 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown