Is HCN4 p.Pro80Ser (c.238C>T) pathogenic?

HCN4 p.Pro80Ser (c.238C>T) is classified Conflicting classifications of pathogenicity in HCN4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-09-13). AlphaMissense: likely benign (0.0679); Very rare (popmax 0.00263%, amr); Associated with Cardiovascular phenotype.

What condition is associated with HCN4 p.Pro80Ser (c.238C>T)?

HCN4 p.Pro80Ser (c.238C>T) is associated with Cardiovascular phenotype, Brugada syndrome 8 (ClinVar).

How common is HCN4 p.Pro80Ser (c.238C>T) in the general population?

HCN4 p.Pro80Ser (c.238C>T) is very rare (popmax 0.00263%, amr) (gnomAD).

What do computational predictors say about HCN4 p.Pro80Ser (c.238C>T)?

AlphaMissense predicts likely benign (score 0.0679) — an in-silico prediction, not a clinical call.

HCN4 p.Pro80Ser

c.238C>T · rs1595837594 · VCV1790541

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0679 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00263%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0679	likely benign
REVEL	0.217	benign-leaning
SaProt	LLR -5.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP -0.18, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 675 bp · p 0.7 · regional, not allelic
Overall
CADD	15.87	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 0.00263% Admixed American · 1/38,018 alleles

Overall 0.000138% 2/1,449,834 alleles · very rare exomes 2/1,297,828 · genomes 0/152,006 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00263%	38,018
Finnishnot grpmax-eligible	0.00232%	43,186

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.Pro80Ser
Coding: c.238C>T
MANE Select: NM_005477
dbSNP: rs1595837594
Type: single nucleotide variant
Location: chr15:73368033 (GRCh38)
Gene constraint: LOEUF 0.571 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 61.86 · 8 PDB
Residue 80: 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.Pro80= 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
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-pro80ser (accessed [today's date]).

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