# NM_000238.4(KCNH2):c.1968C>T (p.Phe656=)

https://sugi.bio/variant/kcnh2-p-phe656

## Summary

**KCNH2 p.Phe656= (c.1968C>T)** is classified **Likely benign** in KCNH2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-12). Very rare (popmax 0.00333%, amr); Associated with Cardiovascular phenotype.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs1238904019 · 5 submitters · 3 linked conditions · very rare (popmax 0.00333%, amr)

## For patients & families {#patients}

This is a change in the KCNH2 gene that is classified as likely benign — not considered disease-causing, submitted by 5 submitters, and is linked to Cardiovascular phenotype.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [KCNH2](https://sugi.bio/atlas/gene/KCNH2/) |
| Protein change (HGVS p.) | p.Phe656= |
| Coding change (HGVS c.) | c.1968C>T |
| MANE Select transcript | [NM_000238](https://www.ncbi.nlm.nih.gov/nuccore/NM_000238) |
| dbSNP | [rs1238904019](https://www.ncbi.nlm.nih.gov/snp/rs1238904019/) |
| Variant type | single nucleotide variant |
| Location | chr7:150951098-150951098 (GRCh38) |
| ClinVar | [VCV1152898](https://www.ncbi.nlm.nih.gov/clinvar/variation/1152898/) |

**All HGVS expressions:** `LRG_288:g.31829C>T`, `LRG_288t1:c.1968C>T`, `LRG_288t2:c.1968C>T`, `LRG_288t3:c.948C>T`, `NC_000007.13:g.150648186G>A`, `NC_000007.14:g.150951098G>A`, `NG_008916.1:g.31829C>T`, `NM_000238.4:c.1968C>T`, `NM_001204798.2:c.948C>T`, `NM_001406753.1:c.1680C>T`, `NM_001406755.1:c.1791C>T`, `NM_001406756.1:c.1680C>T`, `NM_001406757.1:c.1668C>T`, `NM_172056.3:c.1968C>T`, `NM_172057.3:c.948C>T`, `NR_176254.1:n.2376C>T`, `NR_176255.1:n.1249C>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 0.451, GERP -2.86, phastCons 0.975 — weakly conserved position
- CADD: **PHRED 13.48**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.32 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00333%** (amr) · FAF95 0.000878% · FAF99 0.000718% · 2/59,992 in the highest group · 22/1,611,810 alleles overall — very rare (popmax 0.00333%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00333% | 29,996 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,416 |
| European (non-Finnish) | 0.00144% | 69,352 |
| African / African-American | 0.00133% | 74,922 |
| South Asian | 0.0011% | 91,038 |

*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}

**KCNH2** population constraint: LOEUF 0.568, pLI 0.066807, missense-Z 2.4976; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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):

- **long QT syndrome** — Definitive (AD)
- **short QT syndrome** — Definitive (AD)
- **Brugada syndrome** — Disputed (AD)

## Protein context {#protein}

Residue **656** lies in a UniProt-annotated variant site (in lqt2; uncertain significance); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 63.94, 29% of residues very-high.

**24 experimental structure(s)** (PDB): [1BYW](https://www.rcsb.org/structure/1BYW), [1UJL](https://www.rcsb.org/structure/1UJL), [2L0W](https://www.rcsb.org/structure/2L0W), [2L1M](https://www.rcsb.org/structure/2L1M), [2L4R](https://www.rcsb.org/structure/2L4R), [2LE7](https://www.rcsb.org/structure/2LE7).

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

*Describes the biological roles of KCNH2 (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:** KCNH2's established molecular role includes transcription cis-regulatory region binding.


### Pathways affected {#pathways}

KCNH2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Phase 3 - rapid repolarisation](https://reactome.org/content/detail/R-HSA-5576890) | curated |
| [Voltage gated Potassium channels](https://reactome.org/content/detail/R-HSA-1296072) | curated |

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

**Molecular function:** transcription cis-regulatory region binding, inward rectifier potassium channel activity, voltage-gated potassium channel activity, delayed rectifier potassium channel activity, ubiquitin protein ligase binding, identical protein binding.

**Biological process:** potassium ion transport, regulation of membrane potential, positive regulation of DNA-templated transcription, potassium ion homeostasis, cardiac muscle contraction, regulation of membrane repolarization.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-12.

**Submitter consensus:** conflicting (4 Likely benign, 1 Likely Benign).

**Submission history:** 5 submissions (2017–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| All of Us Research Program, National Institutes of Health | Likely Benign | criteria provided, single submitter | clinical testing | 2023-12-01 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2017-12-27 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2021-11-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-12 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-04 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [long QT syndrome](https://sugi.bio/atlas/disease/long-qt-syndrome/), [cardiac rhythm disease](https://sugi.bio/atlas/disease/cardiac-rhythm-disease/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, Long QT syndrome, Cardiac arrhythmia, not specified, Cardiac rhythm disease, Arrhythmia, AllHighlyPenetrant.

## Same-residue context {#hotspot}

Residue **656** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [KCNH2 p.Phe656_Ile663del](/variant/kcnh2-p-phe656-ile663del), [KCNH2 p.Phe656fs](/variant/kcnh2-p-phe656fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related KCNH2 variant pages (same residue, condition, or type): [KCNH2 p.Phe656Leu](/variant/kcnh2-p-phe656leu), [KCNH2 p.Phe656_Ile663del](/variant/kcnh2-p-phe656-ile663del), [KCNH2 c.1129-1G>A](/variant/kcnh2-c-1129-minus-1g-a), [KCNH2 c.1129-2A>G](/variant/kcnh2-c-1129-minus-2a-g), [KCNH2 c.1557+1G>C](/variant/kcnh2-c-1557-plus-1g-c), [KCNH2 c.1945+1G>A](/variant/kcnh2-c-1945-plus-1g-a), [KCNH2 c.1945+6T>C](/variant/kcnh2-c-1945-plus-6t-c), [KCNH2 c.1946-2A>C](/variant/kcnh2-c-1946-minus-2a-c).

### 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 1152898). 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.*