Is HCN4 p.Pro1027= (c.3081C>T) pathogenic?

HCN4 p.Pro1027= (c.3081C>T) is classified Conflicting classifications of pathogenicity in HCN4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-06). Very rare (popmax 0.00306%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with HCN4 p.Pro1027= (c.3081C>T)?

HCN4 p.Pro1027= (c.3081C>T) is associated with Cardiovascular phenotype, sick sinus syndrome 2, autosomal dominant, Brugada syndrome 8 (ClinVar).

How common is HCN4 p.Pro1027= (c.3081C>T) in the general population?

HCN4 p.Pro1027= (c.3081C>T) is very rare (popmax 0.00306%, nfe) (gnomAD).

HCN4 p.Pro1027=

c.3081C>T · rs1226393084 · VCV886650

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00306%, nfe)

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 -0.086	GERP -1.8, phastCons 0.067
Overall
CADD	1.336	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00306% European (non-Finnish) · 34/1,112,466 alleles

Filtering AF 0.0022% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00194%

Overall 0.00252% 37/1,470,794 alleles · very rare exomes 34/1,318,752 · genomes 3/152,042 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00354%	28,258
European (non-Finnish)grpmax	0.00306%	32,720
South Asian	0.00141%	70,856

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.Pro1027=
Coding: c.3081C>T
MANE Select: NM_005477
dbSNP: rs1226393084
Type: single nucleotide variant
Location: chr15:73323012 (GRCh38)
Gene constraint: LOEUF 0.571 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 61.86 · 8 PDB
Residue 1027: 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.Pro1027Ser 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
HCN4 p.Tyr354Cys 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-pro1027 (accessed [today's date]).

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