Is HCN4 p.Pro968= (c.2904G>A) pathogenic?

HCN4 p.Pro968= (c.2904G>A) is classified Likely benign in HCN4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-25). Ultra-rare (popmax 0.0506%, afr); Associated with Cardiovascular phenotype.

What condition is associated with HCN4 p.Pro968= (c.2904G>A)?

HCN4 p.Pro968= (c.2904G>A) is associated with Cardiovascular phenotype, sick sinus syndrome 2, autosomal dominant, Brugada syndrome 8 (ClinVar).

How common is HCN4 p.Pro968= (c.2904G>A) in the general population?

HCN4 p.Pro968= (c.2904G>A) is ultra-rare (popmax 0.0506%, afr) (gnomAD).

HCN4 p.Pro968=

c.2904G>A · rs368145651 · VCV513559

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0506%, afr)

Conditions

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 -7.5	GERP -1.4
Overall
CADD	1.377	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0506% African / African-American · 37/73,140 alleles

Filtering AF 0.0377% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0333%

Overall 0.00362% 56/1,545,152 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0506%	1,977
South Asian	0.00376%	26,601
Remaining individualsnot grpmax-eligible	0.00336%	29,785
East Asian	0.00228%	43,942
Admixed American	0.00198%	50,578
European (non-Finnish)	0.00104%	95,743

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.Pro968=
Coding: c.2904G>A
MANE Select: NM_005477
dbSNP: rs368145651
Type: single nucleotide variant
Location: chr15:73323189 (GRCh38)
Gene constraint: LOEUF 0.571 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 61.86 · 8 PDB
Residue 968: the 'disordered' region

Full HCN4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: sick sinus syndrome 2, autosomal dominant Brugada syndrome 8 epilepsy, idiopathic generalized, susceptibility to, 18

Similar variants

HCN4 p.Pro968Leu Uncertain significance ★★ ⚠ same residue
HCN4 p.Pro968Ser 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-pro968 (accessed [today's date]).

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