Is HCN1 p.Phe420Leu (c.1260C>G) pathogenic?

HCN1 p.Phe420Leu (c.1260C>G) is classified Uncertain significance in HCN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-09). AlphaMissense: likely pathogenic (1); Absent from gnomAD v4.1; Associated with early-infantile DEE.

What condition is associated with HCN1 p.Phe420Leu (c.1260C>G)?

HCN1 p.Phe420Leu (c.1260C>G) is associated with early-infantile DEE (ClinVar).

How common is HCN1 p.Phe420Leu (c.1260C>G) in the general population?

HCN1 p.Phe420Leu (c.1260C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HCN1 p.Phe420Leu (c.1260C>G)?

AlphaMissense predicts likely pathogenic (score 1) — an in-silico prediction, not a clinical call.

HCN1 p.Phe420Leu

c.1260C>G · rs1423833153 · VCV2850962

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

1 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

early-infantile DEE

Computational evidence

Protein change
AlphaMissense	1	likely pathogenic · top 8% in HCN1
REVEL	0.669	pathogenic-leaning
SaProt	LLR -9.99	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.26	constrained · MANE · 343 kb · p 4e-50 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

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: HCN1
Protein: p.Phe420Leu
Coding: c.1260C>G
MANE Select: NM_021072
dbSNP: rs1423833153
Type: single nucleotide variant
Location: chr5:45353217 (GRCh38)
Gene constraint: LOEUF 0.329 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.61 · 17 PDB
Residue 420: an α-helix

Full HCN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

early-infantile DEE — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HCN1 p.Gly391Ser Pathogenic ★★ same condition
HCN1 p.His279Tyr Pathogenic/Likely pathogenic ★★ same condition
HCN1 p.Ser100Phe Pathogenic/Likely pathogenic ★★ same condition
HCN1 c.1230+1G>T Uncertain significance ★★ same condition
HCN1 p.Ala479Thr Uncertain significance ★★ ⚠ same condition
HCN1 p.Ala507Thr Uncertain significance ★★ ⚠ same condition
HCN1 p.Ala670Glu Uncertain significance ★★ same condition
HCN1 p.Ala692Gly 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/hcn1-p-phe420leu (accessed [today's date]).

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