Is HCN2 p.Ser488Phe (c.1463C>T) pathogenic?

HCN2 p.Ser488Phe (c.1463C>T) is classified Uncertain significance in HCN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-05). AlphaMissense: likely pathogenic (0.9909); Very rare (popmax 0.00017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with HCN2 p.Ser488Phe (c.1463C>T)?

HCN2 p.Ser488Phe (c.1463C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HCN2 p.Ser488Phe (c.1463C>T) in the general population?

HCN2 p.Ser488Phe (c.1463C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about HCN2 p.Ser488Phe (c.1463C>T)?

AlphaMissense predicts likely pathogenic (score 0.9909) — an in-silico prediction, not a clinical call.

HCN2 p.Ser488Phe

c.1463C>T · VCV4831974

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9909 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9909	likely pathogenic
REVEL	0.932	strongly pathogenic-leaning
SaProt	LLR -14.69	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 7.5	GERP 2.1, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 23 kb · p 7.3e-31 · regional, not allelic
Overall
CADD	28.6	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

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,784 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,460 alleles · very rare exomes 2/1,461,336 · genomes 0/152,124 · 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.Ser488Phe
Coding: c.1463C>T
MANE Select: NM_001194
Type: single nucleotide variant
Location: chr19:610284 (GRCh38)
Gene constraint: LOEUF 0.627 · pLI 0.18 (gnomAD)
Structure: AlphaFold pLDDT 72.28 · 3 PDB
Residue 488: an α-helix

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.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
HCN2 p.Ala141Val 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-ser488phe (accessed [today's date]).

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