Is HCN4 p.Pro962= (c.2886A>C) pathogenic?

HCN4 p.Pro962= (c.2886A>C) is classified Likely benign in HCN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-22). Very rare (popmax 8.76e-05%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with HCN4 p.Pro962= (c.2886A>C)?

HCN4 p.Pro962= (c.2886A>C) is associated with Cardiovascular phenotype (ClinVar).

How common is HCN4 p.Pro962= (c.2886A>C) in the general population?

HCN4 p.Pro962= (c.2886A>C) is very rare (popmax 8.76e-05%, nfe) (gnomAD).

HCN4 p.Pro962=

c.2886A>C · rs2151214312 · VCV1797219

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.76e-05%, nfe)

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 -7.9	GERP -1.4
Overall
CADD	0.443	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.76e-05% European (non-Finnish) · 1/1,142,034 alleles

Overall 7.23e-05% 1/1,382,482 alleles · very rare

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.Pro962=
Coding: c.2886A>C
MANE Select: NM_005477
dbSNP: rs2151214312
Type: single nucleotide variant
Location: chr15:73323207 (GRCh38)
Gene constraint: LOEUF 0.571 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 61.86 · 8 PDB
Residue 962: 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

Similar variants

HCN4 p.Pro962Thr Uncertain significance ★ ⚠ same residue
HCN4 p.Pro962Leu Uncertain significance ★ ⚠ same residue
HCN4 p.Gly482Arg Pathogenic/Likely pathogenic ★★ same condition
HCN4 p.Tyr481His Pathogenic/Likely pathogenic ★★ same condition
HCN4 c.2143+5G>C Uncertain significance ★★ same condition
HCN4 p.Ala1041Val Uncertain significance ★★ ⚠ same condition
HCN4 p.Ala1045Val Uncertain significance ★★ ⚠ same condition
HCN4 p.Ala1088Thr Uncertain significance ★★ ⚠ 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-pro962 (accessed [today's date]).

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