# NM_001365999.1(SZT2):c.3977C>T (p.Ala1326Val)

https://sugi.bio/variant/szt2-p-ala1326val

## Summary

**SZT2 p.Ala1326Val (c.3977C>T)** is classified **Uncertain significance** in SZT2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-08-20). AlphaMissense: likely pathogenic (0.6368); Very rare (popmax 0.00381%, nfe); Associated with self-limited epilepsy with centrotemporal spikes.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs747241860 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00381%, nfe)

## For patients & families {#patients}

This is a change in the SZT2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to self-limited epilepsy with centrotemporal spikes.

*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 |
| Age of onset (of this condition) | Childhood |
| Clinical trials | 12 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | SZT2 is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Self-limited epilepsy with centrotemporal spikes** (across patients with this condition; presentation varies — frequencies from Orphanet):

- EEG with centrotemporal focal spike waves — Very frequent (99-80%)
- Drooling — Frequent (79-30%)
- Focal hemifacial clonic seizure — Frequent (79-30%)
- Bilateral tonic-clonic seizure with focal onset — Frequent (79-30%)
- Focal-onset seizure — Frequent (79-30%)
- Speech articulation difficulties — Frequent (79-30%)
- Sleep apnea — Frequent (79-30%)
- Laryngospasm — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010287/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SZT2](https://sugi.bio/atlas/gene/SZT2/) |
| Protein change (HGVS p.) | p.Ala1326Val |
| Coding change (HGVS c.) | c.3977C>T |
| MANE Select transcript | [NM_001365999](https://www.ncbi.nlm.nih.gov/nuccore/NM_001365999) |
| dbSNP | [rs747241860](https://www.ncbi.nlm.nih.gov/snp/rs747241860/) |
| Variant type | single nucleotide variant |
| Location | chr1:43428297-43428297 (GRCh38) |
| ClinVar | [VCV433088](https://www.ncbi.nlm.nih.gov/clinvar/variation/433088/) |

**All HGVS expressions:** `NC_000001.10:g.43893968C>T`, `NC_000001.11:g.43428297C>T`, `NG_029091.1:g.43413C>T`, `NM_001365999.1:c.3977C>T`, `NM_015284.4:c.3806C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.6368)
- REVEL 0.647 (pathogenic-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this damaging; SaProt makes no call
- Conservation: phyloP 7.64, GERP 1.72, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.4**. 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.*
- Regional missense constraint: **o/e 0.92** across the covering region of the MANE Select transcript (43,422,165–43,437,222), spanning 15,057 bp. Chi-square p 0.00032. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.59 donor 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 **0.00381%** (nfe) · FAF95 0.00291% · FAF99 0.0026% · 45/1,180,024 in the highest group · 56/1,614,032 alleles overall — very rare (popmax 0.00381%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00937% | 10,672 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,829 |
| European (non-Finnish) (grpmax) | 0.00381% | 26,223 |
| East Asian | 0.00223% | 44,892 |
| South Asian | 0.0011% | 91,090 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**SZT2** population constraint: LOEUF 0.582, pLI 4.7089e-26, missense-Z 4.0315. *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):

- **genetic developmental and epileptic encephalopathy** — Definitive (AR)

## Protein context {#protein}

Residue **1326** lies in a UniProt-annotated variant site (in dee18).

**11 experimental structure(s)** (PDB): [25GE](https://www.rcsb.org/structure/25GE), [25GF](https://www.rcsb.org/structure/25GF), [9O5A](https://www.rcsb.org/structure/9O5A), [9O5D](https://www.rcsb.org/structure/9O5D), [9O5E](https://www.rcsb.org/structure/9O5E), [9V0J](https://www.rcsb.org/structure/9V0J).

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

*Describes the biological roles of SZT2 (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.*


### Pathways affected {#pathways}

SZT2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Amino acids regulate mTORC1](https://reactome.org/content/detail/R-HSA-9639288) | curated |

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

**Biological process:** corpus callosum morphogenesis, cellular response to amino acid starvation, cellular response to glucose starvation, protein localization to lysosome, negative regulation of TORC1 signaling.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-08-20.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Uncertain significance).

**Submission history:** 2 submissions (2017–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Bioinformatics Core, Luxembourg Center for Systems Biomedicine | Pathogenic | no assertion criteria provided | case-control | 2017-01-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-20 |

## Associated conditions {#conditions}

[self-limited epilepsy with centrotemporal spikes](https://sugi.bio/atlas/disease/self-limited-epilepsy-with-centrotemporal-spikes/).

**Reported phenotype names (ClinVar):** Self-limited epilepsy with centrotemporal spikes, not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided, Rolandic epilepsy, Childhood epilepsy with centrotemporal spikes.

## Similar variants {#similar}

Related SZT2 variant pages (same residue, condition, or type): [SZT2 p.Ala1326=](/variant/szt2-p-ala1326), [SZT2 p.Ala1326Thr](/variant/szt2-p-ala1326thr), [SZT2 p.Ala938Thr](/variant/szt2-p-ala938thr), [SZT2 p.Arg1379Trp](/variant/szt2-p-arg1379trp), [SZT2 p.Arg1722His](/variant/szt2-p-arg1722his), [SZT2 p.Arg1839Cys](/variant/szt2-p-arg1839cys), [SZT2 p.Met2629Ile](/variant/szt2-p-met2629ile), [SZT2 p.Thr2980Ile](/variant/szt2-p-thr2980ile).

### 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 2026-10-14); 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 433088). 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.*