HCN2 p.Phe416=
c.1248C>T · VCV4939431
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00988%, sas)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.20 | acceptor loss · deltas |
|---|---|---|
| Pangolin | Δ0.42 | gain · loss 0.30 · SpliceAI calls loss · independent |
| Constraint at this position | ||
| Conservation | phyloP -4.7 | GERP -4.3 |
| Overall | ||
| CADD | 0.422 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00988%
South Asian · 9/91,064 alleles
Filtering AF
0.00514%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00375%
Overall
0.00186%
30/1,612,512 alleles · very rare
exomes 29/1,460,268 · genomes 1/152,244 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.00988% | 10,118 |
| Finnishnot grpmax-eligible | 0.00634% | 15,761 |
| Ashkenazi Jewishnot grpmax-eligible | 0.00338% | 29,600 |
| Remaining individualsnot grpmax-eligible | 0.0032% | 31,216 |
| East Asian | 0.00223% | 44,896 |
| Admixed American | 0.00167% | 60,000 |
| African / African-American | 0.00133% | 74,938 |
| European (non-Finnish) | 0.000932% | 107,272 |
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.Phe416=
- Coding
- c.1248C>T
- MANE Select
- NM_001194
- Type
- single nucleotide variant
- Location
- chr19:607993 (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-phe416 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown