Is HCN2 p.Pro43= (c.129C>T) pathogenic?

HCN2 p.Pro43= (c.129C>T) is classified Likely benign in HCN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-23). Very rare (popmax 0.000209%, nfe); Associated with Inborn genetic diseases.

What condition is associated with HCN2 p.Pro43= (c.129C>T)?

HCN2 p.Pro43= (c.129C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HCN2 p.Pro43= (c.129C>T) in the general population?

HCN2 p.Pro43= (c.129C>T) is very rare (popmax 0.000209%, nfe) (gnomAD).

HCN2 p.Pro43=

c.129C>T · rs2512439365 · VCV1769313

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000209%, nfe)

Conditions

Inborn genetic diseases

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 -1.7	GERP -3.4
Overall
CADD	10.92	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000209% European (non-Finnish) · 1/479,596 alleles

Overall 0.000169% 1/593,128 alleles · very rare exomes 1/457,524 · genomes 0/135,604 · joint denominator

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: HCN2
Protein: p.Pro43=
Coding: c.129C>T
MANE Select: NM_001194
dbSNP: rs2512439365
Type: single nucleotide variant
Location: chr19:590074 (GRCh38)
Gene constraint: LOEUF 0.627 · pLI 0.18 (gnomAD)
Structure: AlphaFold pLDDT 72.28 · 3 PDB
Residue 43: the 'disordered' region

Full HCN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HCN2 p.Pro43Ala Uncertain significance ★ ⚠ same residue
HCN2 p.Pro43Ser Uncertain significance ★ ⚠ same residue
HCN2 p.Arg396His Uncertain significance ★★ ⚠ same condition
HCN2 p.Arg474Cys Uncertain significance ★★ ⚠ same condition
HCN2 p.Asp625Asn Uncertain significance ★★ same condition
HCN2 p.Gly712Asp Uncertain significance ★★ ⚠ same condition
HCN2 p.Pro717Ser Uncertain significance ★★ ⚠ same condition
HCN2 p.Pro777Arg Uncertain significance ★★ ⚠ 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/hcn2-p-pro43 (accessed [today's date]).

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