Is HCN4 p.Pro960= (c.2880A>C) pathogenic?

HCN4 p.Pro960= (c.2880A>C) is classified Likely benign in HCN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-24). Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with HCN4 p.Pro960= (c.2880A>C)?

HCN4 p.Pro960= (c.2880A>C) is associated with Cardiovascular phenotype (ClinVar).

How common is HCN4 p.Pro960= (c.2880A>C) in the general population?

HCN4 p.Pro960= (c.2880A>C) is absent from gnomAD v4.1 (gnomAD).

HCN4 p.Pro960=

c.2880A>C · rs2151214322 · VCV1797165

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 -3.9	GERP -1.4
Overall
CADD	2.248	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HCN4
Protein: p.Pro960=
Coding: c.2880A>C
MANE Select: NM_005477
dbSNP: rs2151214322
Type: single nucleotide variant
Location: chr15:73323213 (GRCh38)
Gene constraint: LOEUF 0.571 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 61.86 · 8 PDB
Residue 960: 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.Pro960Gln 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
HCN4 p.Ala1088Val 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-pro960 (accessed [today's date]).

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