# NM_005477.3(HCN4):c.702C>T (p.Phe234=)

https://sugi.bio/variant/hcn4-p-phe234

## Summary

**HCN4 p.Phe234= (c.702C>T)** is classified **Likely benign** in HCN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-27). Very rare (popmax 0.00267%, afr); Associated with Brugada syndrome 8.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.00267%, afr)

## For patients & families {#patients}

This is a change in the HCN4 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Brugada syndrome 8.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Not applicable |
| Age of onset (of this condition) | Adult, Childhood |
| Prevalence | 1-5 / 10 000 (Europe) |
| Diagnostic panels | HCN4 is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Brugada syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Syncope — Frequent (79-30%)
- Cardiac arrest — Frequent (79-30%)
- Right bundle branch block — Frequent (79-30%)
- ST segment elevation — Frequent (79-30%)
- Tachycardia — Occasional (29-5%)
- Ventricular fibrillation — Occasional (29-5%)
- Paroxysmal ventricular tachycardia — Occasional (29-5%)
- Supraventricular tachycardia — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015622/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [HCN4](https://sugi.bio/atlas/gene/HCN4/) |
| Protein change (HGVS p.) | p.Phe234= |
| Coding change (HGVS c.) | c.702C>T |
| MANE Select transcript | [NM_005477](https://www.ncbi.nlm.nih.gov/nuccore/NM_005477) |
| Variant type | single nucleotide variant |
| Location | chr15:73367569-73367569 (GRCh38) |
| ClinVar | [VCV4755211](https://www.ncbi.nlm.nih.gov/clinvar/variation/4755211/) |

**All HGVS expressions:** `NC_000015.10:g.73367569G>A`, `NC_000015.9:g.73659910G>A`, `NG_009063.1:g.6696C>T`, `NM_005477.3:c.702C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.69, GERP -2.47, phastCons 0.998 — weakly conserved position
- CADD: **PHRED 8.007**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00267%** (afr) · FAF95 0.000443% · FAF99 0.000166% · 2/74,910 in the highest group · 6/1,613,824 alleles overall — very rare (popmax 0.00267%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00267% | 37,455 |
| Admixed American | 0.00167% | 60,008 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,482 |
| South Asian | 0.0011% | 91,086 |
| European (non-Finnish) | 8.47e-05% | 1,180,027 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**HCN4** population constraint: LOEUF 0.571, pLI 0.14903, missense-Z 1.2903. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **sick sinus syndrome 2, autosomal dominant** — Definitive (AD)
- **Brugada syndrome 1** — Disputed (AD)

## Protein context {#protein}

Residue **234** lies in the 'involved in subunit assembly' region; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 61.86, 28% of residues very-high.

**8 experimental structure(s)** (PDB): [2MNG](https://www.rcsb.org/structure/2MNG), [3OTF](https://www.rcsb.org/structure/3OTF), [3U11](https://www.rcsb.org/structure/3U11), [4HBN](https://www.rcsb.org/structure/4HBN), [4KL1](https://www.rcsb.org/structure/4KL1), [4NVP](https://www.rcsb.org/structure/4NVP).

## What this gene does {#gene-function}

*Describes the biological roles of HCN4 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** HCN4's established molecular role includes intracellularly cAMP-activated cation channel activity. p.Phe234= falls in the involved in subunit assembly region.


### Pathways affected {#pathways}

HCN4 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [HCN channels](https://reactome.org/content/detail/R-HSA-1296061) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** intracellularly cAMP-activated cation channel activity, voltage-gated sodium channel activity, voltage-gated potassium channel activity, voltage-gated potassium channel activity involved in SA node cell action potential depolarization.

**Biological process:** regulation of heart rate, regulation of membrane depolarization, monoatomic cation transport, sodium ion transmembrane transport, regulation of membrane potential, regulation of cardiac muscle contraction.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-27.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-27 |

## Associated conditions {#conditions}

[Brugada syndrome 8](https://sugi.bio/atlas/disease/brugada-syndrome-8/).

**Reported phenotype names (ClinVar):** Brugada syndrome 8.

## Similar variants {#similar}

Related HCN4 variant pages (same residue, condition, or type): [HCN4 p.Phe234Leu](/variant/hcn4-p-phe234leu), [HCN4 c.2143+1G>A](/variant/hcn4-c-2143-plus-1g-a), [HCN4 p.Ala485Val](/variant/hcn4-p-ala485val), [HCN4 p.Arg375Cys](/variant/hcn4-p-arg375cys), [HCN4 p.Gly480Ser](/variant/hcn4-p-gly480ser), [HCN4 p.Gly480Val](/variant/hcn4-p-gly480val), [HCN4 p.Gly482Arg](/variant/hcn4-p-gly482arg), [HCN4 p.Tyr354Cys](/variant/hcn4-p-tyr354cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 4755211). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*