Is HCN2 p.Pro30Ser (c.88C>T) pathogenic?

HCN2 p.Pro30Ser (c.88C>T) is classified Uncertain significance in HCN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely benign (0.0932); Ultra-rare (popmax 0.0348%, amr); Associated with Inborn genetic diseases.

What condition is associated with HCN2 p.Pro30Ser (c.88C>T)?

HCN2 p.Pro30Ser (c.88C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HCN2 p.Pro30Ser (c.88C>T) in the general population?

HCN2 p.Pro30Ser (c.88C>T) is ultra-rare (popmax 0.0348%, amr) (gnomAD).

What do computational predictors say about HCN2 p.Pro30Ser (c.88C>T)?

AlphaMissense predicts likely benign (score 0.0932) — an in-silico prediction, not a clinical call.

HCN2 p.Pro30Ser

c.88C>T · VCV4269172

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0932 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0348%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0932	likely benign
REVEL	0.268	benign-leaning
SaProt	LLR -9.19	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 0.77	GERP -2.6, phastCons 0.001
Regional constraint	o/e 1.20	unconstrained · MANE · 493 bp · p 0.0079 · regional, not allelic
Overall
CADD	15.19	PHRED · no single calibrated threshold — expert panels disagree

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

Grpmax group 0.0348% Admixed American · 5/14,378 alleles

Filtering AF 0.0136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00882%

Overall 0.00105% 6/571,292 alleles · ultra-rare exomes 1/440,160 · genomes 5/131,132 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0348%	2,876
South Asian	0.00767%	13,034

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.Pro30Ser
Coding: c.88C>T
MANE Select: NM_001194
Type: single nucleotide variant
Location: chr19:590033 (GRCh38)
Gene constraint: LOEUF 0.627 · pLI 0.18 (gnomAD)
Structure: AlphaFold pLDDT 72.28 · 3 PDB
Residue 30: 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.Pro30= Likely benign ★ 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
HCN2 p.Ala141Ser Likely benign ★★ 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-pro30ser (accessed [today's date]).

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