Is HCN4 p.Pro165= (c.495G>A) pathogenic?

HCN4 p.Pro165= (c.495G>A) is classified Likely benign in HCN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-31). Very rare (popmax 0.000979%, nfe); Associated with Brugada syndrome 8.

What condition is associated with HCN4 p.Pro165= (c.495G>A)?

HCN4 p.Pro165= (c.495G>A) is associated with Brugada syndrome 8 (ClinVar).

How common is HCN4 p.Pro165= (c.495G>A) in the general population?

HCN4 p.Pro165= (c.495G>A) is very rare (popmax 0.000979%, nfe) (gnomAD).

How is Brugada syndrome inherited?

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

HCN4 p.Pro165=

c.495G>A · rs2151228505 · VCV1654839

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000979%, nfe)

Conditions

Brugada syndrome 8

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 -0.18	GERP -0.056, phastCons 0.93
Overall
CADD	11.9	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000979% European (non-Finnish) · 11/1,124,078 alleles

Filtering AF 0.000525% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000384%

Overall 0.00074% 11/1,486,268 alleles · very rare exomes 11/1,335,030 · genomes 0/151,238 · joint denominator

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.Pro165=
Coding: c.495G>A
MANE Select: NM_005477
dbSNP: rs2151228505
Type: single nucleotide variant
Location: chr15:73367776 (GRCh38)
Gene constraint: LOEUF 0.571 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 61.86 · 8 PDB
Residue 165: 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.Pro165Ser Uncertain significance ★★ ⚠ same residue
HCN4 p.Pro165Gln 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
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-pro165 (accessed [today's date]).

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