Is HCN4 p.Arg1069Trp (c.3205C>T) pathogenic?

HCN4 p.Arg1069Trp (c.3205C>T) is classified Conflicting classifications of pathogenicity in HCN4 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-28). AlphaMissense: likely benign (0.1051); Very rare (popmax 0.00364%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with HCN4 p.Arg1069Trp (c.3205C>T)?

HCN4 p.Arg1069Trp (c.3205C>T) is associated with Cardiovascular phenotype, sick sinus syndrome 2, autosomal dominant, Brugada syndrome 8 (ClinVar).

How common is HCN4 p.Arg1069Trp (c.3205C>T) in the general population?

HCN4 p.Arg1069Trp (c.3205C>T) is very rare (popmax 0.00364%, nfe) (gnomAD).

What do computational predictors say about HCN4 p.Arg1069Trp (c.3205C>T)?

AlphaMissense predicts likely benign (score 0.1051) — an in-silico prediction, not a clinical call.

HCN4 p.Arg1069Trp

c.3205C>T · rs770658894 · VCV840097

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1051 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00364%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1051	likely benign
REVEL	0.373	indeterminate
SaProt	LLR -8.78	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -2.5, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 1,246 bp · p 0.027 · regional, not allelic
Overall
CADD	19.99	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00364% European (non-Finnish) · 40/1,100,160 alleles

Filtering AF 0.00274% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00331% 48/1,450,624 alleles · very rare exomes 43/1,298,642 · genomes 5/151,982 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00535%	18,703
European (non-Finnish)grpmax	0.00364%	27,504
African / African-American	0.00282%	35,493
Admixed American	0.00274%	36,522
Finnishnot grpmax-eligible	0.00215%	46,492
South Asian	0.00144%	69,296

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg1069Trp
Coding: c.3205C>T
MANE Select: NM_005477
dbSNP: rs770658894
Type: single nucleotide variant
Location: chr15:73322888 (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

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.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-arg1069trp (accessed [today's date]).

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