Is HCN2 p.Arg321= (c.963C>T) pathogenic?

HCN2 p.Arg321= (c.963C>T) is classified Benign in HCN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-03-26). Common (popmax 35.1%, sas) — too common for a highly-penetrant pathogenic allele.

HCN2 p.Arg321=

Q: How common is HCN2 p.Arg321= (c.963C>T) in the general population?

HCN2 p.Arg321= (c.963C>T) is common (popmax 35.1%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.963C>T · rs55780677 · VCV1277714

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 35.1%, sas) — 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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -12	GERP -3.7
Overall
CADD	7.899	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 35.1% South Asian · 31,937/91,050 alleles

Filtering AF 34.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 34.6%

Overall 13.1% 211,111/1,612,084 alleles · common exomes 187,384/1,459,994 · genomes 23,727/152,090 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	35.1%	3
East Asian	28.2%	4
African / African-American	25%	4
Middle Eastern	18.1%	6
Remaining individualsnot grpmax-eligible	14.3%	7
European (non-Finnish)	10.5%	10
Admixed American	10.3%	10
Amishnot grpmax-eligible	10.1%	10
Ashkenazi Jewishnot grpmax-eligible	9.08%	11
Finnishnot grpmax-eligible	7.53%	13

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.Arg321=
Coding: c.963C>T
MANE Select: NM_001194
dbSNP: rs55780677
Type: single nucleotide variant
Location: chr19:603874 (GRCh38)
Gene constraint: LOEUF 0.627 · pLI 0.18 (gnomAD)
Structure: AlphaFold pLDDT 72.28 · 3 PDB

Full HCN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HCN2 p.Arg321His Uncertain significance ★ ⚠ same residue
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

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-arg321 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown