HCN4 p.Pro351=
c.1053C>T · rs773287506 · VCV1174971
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 6 submitters
gnomAD v4.1
Rare
very rare (popmax 0.00333%, amr)
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 -5.5 | GERP -3.7 |
| Overall | ||
| CADD | 2.588 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00333%
Admixed American · 2/60,008 alleles
Filtering AF
0.000953%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000787%
Overall
0.00149%
24/1,614,082 alleles · very rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.00333% | 30,004 |
| African / African-American | 0.00267% | 37,460 |
| Finnishnot grpmax-eligible | 0.00156% | 64,038 |
| European (non-Finnish) | 0.00153% | 65,559 |
| South Asian | 0.0011% | 91,080 |
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.Pro351=
- Coding
- c.1053C>T
- MANE Select
- NM_005477
- dbSNP
- rs773287506
- Type
- single nucleotide variant
- Location
- chr15:73343541 (GRCh38)
- Gene constraint
- LOEUF 0.571 · pLI 0.15 (gnomAD)
- Structure
- AlphaFold pLDDT 61.86 · 8 PDB
Similar variants
- 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
- HCN4 p.Tyr354Cys Pathogenic/Likely pathogenic ★★ same condition
- HCN4 p.Tyr481Cys 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-pro351 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown