Is HCN4 p.Pro6= (c.18G>T) pathogenic?

HCN4 p.Pro6= (c.18G>T) is classified Likely benign in HCN4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-14). Ultra-rare (popmax 0.0262%, sas); Associated with Cardiovascular phenotype.

What condition is associated with HCN4 p.Pro6= (c.18G>T)?

HCN4 p.Pro6= (c.18G>T) is associated with Cardiovascular phenotype, Brugada syndrome 8 (ClinVar).

How common is HCN4 p.Pro6= (c.18G>T) in the general population?

HCN4 p.Pro6= (c.18G>T) is ultra-rare (popmax 0.0262%, sas) (gnomAD).

HCN4 p.Pro6=

c.18G>T · rs771607645 · VCV756493

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0262%, sas)

Conditions

Cardiovascular phenotype

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 5.4	GERP -0.21, phastCons 1
Overall
CADD	14.99	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0262% South Asian · 21/80,058 alleles

Filtering AF 0.0175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00174% 26/1,498,120 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0262%	3,812
Middle Eastern	0.019%	5,266
Remaining individualsnot grpmax-eligible	0.00517%	19,341
European (non-Finnish)	8.87e-05%	1,126,984

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.Pro6=
Coding: c.18G>T
MANE Select: NM_005477
dbSNP: rs771607645
Type: single nucleotide variant
Location: chr15:73368253 (GRCh38)
Gene constraint: LOEUF 0.571 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 61.86 · 8 PDB
Residue 6: 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: Brugada syndrome 8

Similar variants

HCN4 p.Pro6Arg Uncertain significance ★★ ⚠ same residue
HCN4 p.Pro6Gln Uncertain significance ★★ ⚠ same residue
HCN4 p.Pro6Leu Uncertain significance ★ ⚠ same residue
HCN4 p.Pro6Ser 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-pro6 (accessed [today's date]).

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