Is HCN4 p.Arg1069fs (c.3206_3212del) pathogenic?

HCN4 p.Arg1069fs (c.32063212del) is classified Uncertain significance in HCN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-08). Associated with Brugada syndrome 8.

What condition is associated with HCN4 p.Arg1069fs (c.3206_3212del)?

HCN4 p.Arg1069fs (c.3206_3212del) is associated with Brugada syndrome 8 (ClinVar).

How is Brugada syndrome inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

HCN4 p.Arg1069fs

c.3206_3212del · VCV4734162

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

Brugada syndrome 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (8 of 8) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -5	GERP -2.5

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: HCN4
Protein: p.Arg1069fs
Coding: c.3206_3212del
MANE Select: NM_005477
Type: Deletion
Location: chr15:73322881 (GRCh38)
Gene constraint: LOEUF 0.571 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 61.86 · 8 PDB
Residue 1069: the 'disordered' region

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

Disease context

Brugada syndrome 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Brugada syndrome (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

HCN4 p.Arg1069Gln Uncertain significance ★★ ⚠ same residue
HCN4 p.Arg1069Gly Uncertain significance ★ ⚠ same residue
HCN4 p.Arg1069Leu Uncertain significance ★ ⚠ same residue
HCN4 p.Arg1069Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
HCN4 p.Ala948fs Uncertain significance ★★ same condition
HCN4 p.Arg1140fs Uncertain significance ★★ same condition
HCN4 p.Gln1064_Pro1072del Uncertain significance ★★ same condition
HCN4 p.Leu1167_Phe1168del 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-arg1069fs (accessed [today's date]).

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