Is HCN4 p.Arg1069Gln (c.3206G>A) pathogenic?

HCN4 p.Arg1069Gln (c.3206G>A) is classified Uncertain significance in HCN4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-14). AlphaMissense: likely benign (0.0793); Very rare (popmax 0.00553%, amr); Associated with Cardiovascular phenotype.

What condition is associated with HCN4 p.Arg1069Gln (c.3206G>A)?

HCN4 p.Arg1069Gln (c.3206G>A) is associated with Cardiovascular phenotype, sick sinus syndrome 2, autosomal dominant, Brugada syndrome 8 (ClinVar).

How common is HCN4 p.Arg1069Gln (c.3206G>A) in the general population?

HCN4 p.Arg1069Gln (c.3206G>A) is very rare (popmax 0.00553%, amr) (gnomAD).

What do computational predictors say about HCN4 p.Arg1069Gln (c.3206G>A)?

AlphaMissense predicts likely benign (score 0.0793) — an in-silico prediction, not a clinical call.

HCN4 p.Arg1069Gln

c.3206G>A · rs760242560 · VCV1348490

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0793 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00553%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0793	likely benign
REVEL	0.272	benign-leaning
SaProt	LLR -6.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 0.1, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 1,246 bp · p 0.027 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00553% Admixed American · 2/36,164 alleles

Filtering AF 0.000916% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000343%

Overall 0.000696% 10/1,435,946 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00553%	18,082
South Asian	0.00297%	33,645
European (non-Finnish)	0.00055%	181,813

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.Arg1069Gln
Coding: c.3206G>A
MANE Select: NM_005477
dbSNP: rs760242560
Type: single nucleotide variant
Location: chr15:73322887 (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

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.Arg1069Gly Uncertain significance ★ ⚠ same residue
HCN4 p.Arg1069Leu Uncertain significance ★ ⚠ same residue
HCN4 p.Arg1069Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
HCN4 p.Arg1069fs 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

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-arg1069gln (accessed [today's date]).

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