Is HCN2 p.Ala726Val (c.2177C>T) pathogenic?

HCN2 p.Ala726Val (c.2177C>T) is classified Likely benign in HCN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-30). AlphaMissense: ambiguous (0.3619); Ultra-rare (popmax 0.0227%, nfe); Associated with Inborn genetic diseases.

What condition is associated with HCN2 p.Ala726Val (c.2177C>T)?

HCN2 p.Ala726Val (c.2177C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HCN2 p.Ala726Val (c.2177C>T) in the general population?

HCN2 p.Ala726Val (c.2177C>T) is ultra-rare (popmax 0.0227%, nfe) (gnomAD).

What do computational predictors say about HCN2 p.Ala726Val (c.2177C>T)?

AlphaMissense predicts ambiguous (score 0.3619) — an in-silico prediction, not a clinical call.

HCN2 p.Ala726Val

c.2177C>T · VCV3283626

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3619 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3619	ambiguous
REVEL	0.32	indeterminate
SaProt	LLR -7.79	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 0.5, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 2,457 bp · p 0.0027 · regional, not allelic
Overall
CADD	25.2	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

Grpmax group 0.0227% European (non-Finnish) · 266/1,173,304 alleles

Filtering AF 0.0204% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0195%

Overall 0.0176% 280/1,593,468 alleles · ultra-rare exomes 264/1,441,600 · genomes 16/151,868 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0227%	4,411
Middle Eastern	0.0212%	4,708
Remaining individualsnot grpmax-eligible	0.0179%	5,597
African / African-American	0.00269%	37,145

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.Ala726Val
Coding: c.2177C>T
MANE Select: NM_001194
Type: single nucleotide variant
Location: chr19:615981 (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

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-ala726val (accessed [today's date]).

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