Is HCN4 p.Phe613= (c.1839C>T) pathogenic?

HCN4 p.Phe613= (c.1839C>T) is classified Benign in HCN4 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). Common (popmax 6.84%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

What condition is associated with HCN4 p.Phe613= (c.1839C>T)?

HCN4 p.Phe613= (c.1839C>T) is associated with Cardiovascular phenotype, sick sinus syndrome 2, autosomal dominant, Brugada syndrome 8 (ClinVar).

HCN4 p.Phe613=

Q: How common is HCN4 p.Phe613= (c.1839C>T) in the general population?

HCN4 p.Phe613= (c.1839C>T) is common (popmax 6.84%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1839C>T · rs117731813 · VCV137541

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Common

common (popmax 6.84%, eas) — too common for a highly-penetrant pathogenic allele

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 -6.4	GERP -3.7
Overall
CADD	8.674	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.84% East Asian · 3,069/44,868 alleles

Filtering AF 6.64% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.56%

Overall 0.615% 9,928/1,614,214 alleles · common exomes 8,226/1,461,892 · genomes 1,702/152,322 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	6.84%	15
Admixed American	6.32%	16
Finnishnot grpmax-eligible	2.74%	37
Remaining individualsnot grpmax-eligible	0.984%	102
South Asian	0.292%	342
Middle Eastern	0.132%	758
African / African-American	0.111%	904
European (non-Finnish)	0.0288%	3,471
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869

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.Phe613=
Coding: c.1839C>T
MANE Select: NM_005477
dbSNP: rs117731813
Type: single nucleotide variant
Location: chr15:73325094 (GRCh38)
Gene constraint: LOEUF 0.571 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 61.86 · 8 PDB
Residue 613: a β-strand

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.Phe613Leu 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-phe613 (accessed [today's date]).

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