Is HCN2 p.Ser297Pro (c.889T>C) pathogenic?

HCN2 p.Ser297Pro (c.889T>C) is classified Uncertain significance in HCN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-07). AlphaMissense: likely pathogenic (0.9985); Absent from gnomAD v4.1.

How common is HCN2 p.Ser297Pro (c.889T>C) in the general population?

HCN2 p.Ser297Pro (c.889T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HCN2 p.Ser297Pro (c.889T>C)?

AlphaMissense predicts likely pathogenic (score 0.9985) — an in-silico prediction, not a clinical call.

HCN2 p.Ser297Pro

c.889T>C · VCV4886639

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9985 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9985	likely pathogenic · top 10% in HCN2
REVEL	0.847	moderately pathogenic-leaning
SaProt	LLR -15.82	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.91, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 23 kb · p 7.3e-31 · regional, not allelic
Overall
CADD	30.0	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: HCN2
Protein: p.Ser297Pro
Coding: c.889T>C
MANE Select: NM_001194
Type: single nucleotide variant
Location: chr19:603800 (GRCh38)
Gene constraint: LOEUF 0.627 · pLI 0.18 (gnomAD)
Structure: AlphaFold pLDDT 72.28 · 3 PDB

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

Similar variants

HCN2 p.Met374Leu Pathogenic/Likely pathogenic ★★ same type
HCN2 p.Arg264Cys Uncertain significance ★★ ⚠ same type
HCN2 p.Arg396His Uncertain significance ★★ ⚠ same type
HCN2 p.Arg474Cys Uncertain significance ★★ ⚠ same type
HCN2 p.Asp502Asn Uncertain significance ★★ ⚠ same type
HCN2 p.Asp625Asn Uncertain significance ★★ same type
HCN2 p.Glu148Val Uncertain significance ★★ ⚠ same type
HCN2 p.Gly712Asp Uncertain significance ★★ ⚠ same type

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-ser297pro (accessed [today's date]).

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