HCN2 p.Pro389=
c.1167T>C · rs12981860 · VCV1241053
Benign
Multiple submitters
Classification
Benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Common
common (popmax 75.4%, eas) — too common for a highly-penetrant pathogenic allele
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 0.029 | GERP -2, phastCons 0.81 |
| Overall | ||
| CADD | 10.2 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
75.4%
East Asian · 33,805/44,844 alleles
Filtering AF
74.7%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 74.4%
Overall
61.7%
993,295/1,610,438 alleles · common
exomes 902,798/1,458,770 · genomes 90,497/151,668 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 75.4% | 1 |
| Ashkenazi Jewishnot grpmax-eligible | 70% | 1 |
| European (non-Finnish) | 62.5% | 2 |
| Remaining individualsnot grpmax-eligible | 62.2% | 2 |
| Finnishnot grpmax-eligible | 61.5% | 2 |
| Middle Eastern | 59.9% | 2 |
| African / African-American | 56% | 2 |
| Amishnot grpmax-eligible | 53.2% | 2 |
| Admixed American | 52.4% | 2 |
| South Asian | 52.1% | 2 |
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
- HCN2
- Protein
- p.Pro389=
- Coding
- c.1167T>C
- MANE Select
- NM_001194
- dbSNP
- rs12981860
- Type
- single nucleotide variant
- Location
- chr19:605171 (GRCh38)
- Gene constraint
- LOEUF 0.627 · pLI 0.18 (gnomAD)
- Structure
- AlphaFold pLDDT 72.28 · 3 PDB
Similar variants
- HCN2 p.Met374Leu Pathogenic/Likely pathogenic ★★ same type
- HCN2 p.Arg264Cys Uncertain significance ★★ ⚠ same type
- HCN2 p.Arg396His Uncertain significance ★★ ⚠ same type
- HCN2 p.Arg474Cys Uncertain significance ★★ ⚠ same type
- HCN2 p.Asp502Asn Uncertain significance ★★ ⚠ same type
- HCN2 p.Asp625Asn Uncertain significance ★★ same type
- HCN2 p.Glu148Val Uncertain significance ★★ ⚠ same type
- HCN2 p.Gly712Asp Uncertain significance ★★ ⚠ same type
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/hcn2-p-pro389 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown