# NM_198503.5(KCNT2):c.2028A>G (p.Pro676=)

https://sugi.bio/variant/kcnt2-p-pro676

## Summary

**KCNT2 p.Pro676= (c.2028A>G)** is classified **Likely benign** in KCNT2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-09-10). Very rare (popmax 0.000427%, nfe); Associated with KCNT2-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · 1 submitter · 1 linked condition · very rare (popmax 0.000427%, nfe)

## For patients & families {#patients}

This is a change in the KCNT2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to KCNT2-related disorder.

*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 | [KCNT2](https://sugi.bio/atlas/gene/KCNT2/) |
| Protein change (HGVS p.) | p.Pro676= |
| Coding change (HGVS c.) | c.2028A>G |
| MANE Select transcript | [NM_198503](https://www.ncbi.nlm.nih.gov/nuccore/NM_198503) |
| Variant type | single nucleotide variant |
| Location | chr1:196331231-196331231 (GRCh38) |
| ClinVar | [VCV3355510](https://www.ncbi.nlm.nih.gov/clinvar/variation/3355510/) |

**All HGVS expressions:** `NC_000001.10:g.196300361T>C`, `NC_000001.11:g.196331231T>C`, `NM_001287819.3:c.2028A>G`, `NM_001287820.3:c.1878A>G`, `NM_198503.5:c.2028A>G`, `NR_146057.2:n.2050A>G`, `NR_146058.2:n.2159A>G`

## 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 -1.018, GERP -3.82, phastCons 0.003 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 6.301**. 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 (T>G, Δ0.35 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 **0.000427%** (nfe) · FAF95 0.000125% · FAF99 9.1e-05% · 5/1,171,270 in the highest group · 5/1,604,000 alleles overall — very rare (popmax 0.000427%, nfe).

*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}

**KCNT2** population constraint: LOEUF 0.744, pLI 0.00014381, missense-Z 2.9246. *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):

- **complex neurodevelopmental disorder** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 76.42, 35% of residues very-high.

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

*Describes the biological roles of KCNT2 (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:** KCNT2's established molecular role includes intracellular sodium-activated potassium channel activity.


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

**Molecular function:** intracellular sodium-activated potassium channel activity, chloride-activated potassium channel activity.

**Biological process:** potassium ion export across plasma membrane.

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-09-10.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2024-09-10 |

## Associated conditions {#conditions}

[KCNT2-related disorder](https://sugi.bio/atlas/disease/kcnt2-related-disorder/).

**Reported phenotype names (ClinVar):** KCNT2-related disorder, KCNT2-related condition.

## Similar variants {#similar}

Related KCNT2 variant pages (same residue, condition, or type): [KCNT2 c.175+1G>T](/variant/kcnt2-c-175-plus-1g-t), [KCNT2 p.Phe240Leu](/variant/kcnt2-p-phe240leu), [KCNT2 p.Arg1020Lys](/variant/kcnt2-p-arg1020lys), [KCNT2 p.Arg740Lys](/variant/kcnt2-p-arg740lys), [KCNT2 p.Leu371Phe](/variant/kcnt2-p-leu371phe), [KCNT2 p.Asn40Lys](/variant/kcnt2-p-asn40lys), [KCNT2 p.Leu1084=](/variant/kcnt2-p-leu1084), [KCNT2 p.Ter1136=](/variant/kcnt2-p-ter1136).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 3355510). 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.*