Is HCN4 p.Ser970Pro (c.2908T>C) pathogenic?

HCN4 p.Ser970Pro (c.2908T>C) is classified Uncertain significance in HCN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-28). AlphaMissense: likely benign (0.0887); Very rare (popmax 8.7e-05%, nfe); Associated with Brugada syndrome 8.

What condition is associated with HCN4 p.Ser970Pro (c.2908T>C)?

HCN4 p.Ser970Pro (c.2908T>C) is associated with Brugada syndrome 8 (ClinVar).

How common is HCN4 p.Ser970Pro (c.2908T>C) in the general population?

HCN4 p.Ser970Pro (c.2908T>C) is very rare (popmax 8.7e-05%, nfe) (gnomAD).

How is Brugada syndrome inherited?

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

What do computational predictors say about HCN4 p.Ser970Pro (c.2908T>C)?

AlphaMissense predicts likely benign (score 0.0887) — an in-silico prediction, not a clinical call.

HCN4 p.Ser970Pro

c.2908T>C · rs2549068452 · VCV2095366

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0887 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.7e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Brugada syndrome 8

Computational evidence

Protein change
AlphaMissense	0.0887	likely benign
REVEL	0.303	indeterminate
SaProt	LLR -5.18	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 0.71, phastCons 0.51
Regional constraint	o/e 1.09	unconstrained · MANE · 1,246 bp · p 0.027 · regional, not allelic
Overall
CADD	16.2	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 8.7e-05% European (non-Finnish) · 1/1,149,784 alleles

Overall 7.17e-05% 1/1,395,524 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.Ser970Pro
Coding: c.2908T>C
MANE Select: NM_005477
dbSNP: rs2549068452
Type: single nucleotide variant
Location: chr15:73323185 (GRCh38)
Gene constraint: LOEUF 0.571 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 61.86 · 8 PDB
Residue 970: 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.Ser970Phe Uncertain significance ★★ ⚠ same residue
HCN4 p.Ser970= Likely benign ★ 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
HCN4 p.Gly480Val Likely pathogenic ★★ same condition
HCN4 p.Gly482Arg 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-ser970pro (accessed [today's date]).

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