Is SZT2 p.Ala1326Val (c.3977C>T) pathogenic?

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.

What condition is associated with SZT2 p.Ala1326Val (c.3977C>T)?

SZT2 p.Ala1326Val (c.3977C>T) is associated with self-limited epilepsy with centrotemporal spikes (ClinVar).

How common is SZT2 p.Ala1326Val (c.3977C>T) in the general population?

SZT2 p.Ala1326Val (c.3977C>T) is very rare (popmax 0.00381%, nfe) (gnomAD).

What do computational predictors say about SZT2 p.Ala1326Val (c.3977C>T)?

AlphaMissense predicts likely pathogenic (score 0.6368) — an in-silico prediction, not a clinical call.

SZT2 p.Ala1326Val

Q: How is Self-limited epilepsy with centrotemporal spikes inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.3977C>T · rs747241860 · VCV433088

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6368 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00381%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

self-limited epilepsy with centrotemporal spikes

Computational evidence

Protein change
AlphaMissense	0.6368	likely pathogenic
REVEL	0.647	pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.59 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 15 kb · p 0.00032 · regional, not allelic
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00381% European (non-Finnish) · 45/1,180,024 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00347% 56/1,614,032 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00937%	10,672
Remaining individualsnot 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 above it. 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.

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: SZT2
Protein: p.Ala1326Val
Coding: c.3977C>T
MANE Select: NM_001365999
dbSNP: rs747241860
Type: single nucleotide variant
Location: chr1:43428297 (GRCh38)
Gene constraint: LOEUF 0.582 · pLI <0.01 (gnomAD)
Residue 1326: a UniProt-annotated variant site (in dee18)

Full SZT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

self-limited epilepsy with centrotemporal spikes — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Self-limited epilepsy with centrotemporal spikes (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

SZT2 p.Ala1326= Likely benign ★★ same residue
SZT2 p.Ala1326Thr Uncertain significance ★ same residue
SZT2 p.Ala938Thr Uncertain significance ★★ ⚠ same condition
SZT2 p.Arg1379Trp Uncertain significance ★★ ⚠ same condition
SZT2 p.Arg1722His Uncertain significance ★★ ⚠ same condition
SZT2 p.Arg1839Cys Uncertain significance ★★ ⚠ same condition
SZT2 p.Met2629Ile Uncertain significance ★★ ⚠ same condition
SZT2 p.Thr2980Ile Uncertain significance ★★ ⚠ 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/szt2-p-ala1326val (accessed [today's date]).

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