Is HCN4 p.Phe234Leu (c.702C>A) pathogenic?

HCN4 p.Phe234Leu (c.702C>A) is classified Uncertain significance in HCN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-29). AlphaMissense: likely pathogenic (0.9884); Absent from gnomAD v4.1; Associated with Brugada syndrome 8.

What condition is associated with HCN4 p.Phe234Leu (c.702C>A)?

HCN4 p.Phe234Leu (c.702C>A) is associated with Brugada syndrome 8 (ClinVar).

How common is HCN4 p.Phe234Leu (c.702C>A) in the general population?

HCN4 p.Phe234Leu (c.702C>A) is absent from gnomAD v4.1 (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.Phe234Leu (c.702C>A)?

AlphaMissense predicts likely pathogenic (score 0.9884) — an in-silico prediction, not a clinical call.

HCN4 p.Phe234Leu

c.702C>A · rs775592338 · VCV2850630

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9884 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Brugada syndrome 8

Computational evidence

Protein change
AlphaMissense	0.9884	likely pathogenic
REVEL	0.369	indeterminate
SaProt	LLR -10.99	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.69	GERP -2.5, phastCons 1
Regional constraint	o/e 0.40	unconstrained · MANE · 24 kb · p 1.2e-11 · regional, not allelic
Overall
CADD	19.18	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HCN4
Protein: p.Phe234Leu
Coding: c.702C>A
MANE Select: NM_005477
dbSNP: rs775592338
Type: single nucleotide variant
Location: chr15:73367569 (GRCh38)
Gene constraint: LOEUF 0.571 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 61.86 · 8 PDB
Residue 234: the 'involved in subunit assembly' region; a β-strand

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.Phe234= 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-phe234leu (accessed [today's date]).

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