Is SLC6A1 p.Val125Met (c.373G>A) pathogenic?

SLC6A1 p.Val125Met (c.373G>A) is classified Pathogenic in SLC6A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-30). AlphaMissense: likely pathogenic (0.9443); Very rare (popmax 8.52e-05%, nfe); Associated with epilepsy with myoclonic atonic seizures.

What condition is associated with SLC6A1 p.Val125Met (c.373G>A)?

SLC6A1 p.Val125Met (c.373G>A) is associated with epilepsy with myoclonic atonic seizures (ClinVar).

How common is SLC6A1 p.Val125Met (c.373G>A) in the general population?

SLC6A1 p.Val125Met (c.373G>A) is very rare (popmax 8.52e-05%, nfe) (gnomAD).

How is Epilepsy with myoclonic-atonic seizures inherited?

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

What do computational predictors say about SLC6A1 p.Val125Met (c.373G>A)?

AlphaMissense predicts likely pathogenic (score 0.9443) — an in-silico prediction, not a clinical call.

SLC6A1 p.Val125Met

c.373G>A · rs1574893965 · VCV650130

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9443 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.52e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epilepsy with myoclonic atonic seizures

Computational evidence

Protein change
AlphaMissense	0.9443	likely pathogenic ✓ concordant with ClinVar
REVEL	0.765	pathogenic-leaning
SaProt	LLR -9.63	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.32	constrained · MANE · 1,313 bp · p 9.3e-15 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.52e-05% European (non-Finnish) · 1/1,173,180 alleles

Overall 6.22e-05% 1/1,606,592 alleles · very rare exomes 1/1,454,282 · genomes 0/152,310 · joint denominator

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: SLC6A1
Protein: p.Val125Met
Coding: c.373G>A
MANE Select: NM_003042
dbSNP: rs1574893965
Type: single nucleotide variant
Location: chr3:11018600 (GRCh38)
Gene constraint: LOEUF 0.153 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 88.57 · 5 PDB
Residue 125: an α-helix

Full SLC6A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

epilepsy with myoclonic atonic seizures — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Epilepsy with myoclonic-atonic seizures (Orphanet):

Inheritance: Unknown
Onset: Childhood

Similar variants

SLC6A1 c.1192-2A>G Pathogenic/Likely pathogenic ★★ same condition
SLC6A1 c.1528-1G>A Pathogenic ★★ same condition
SLC6A1 p.Ala288Val Pathogenic/Likely pathogenic ★★ same condition
SLC6A1 p.Ala357Val Pathogenic ★★ ⚠ same condition
SLC6A1 p.Arg44Trp Pathogenic/Likely pathogenic ★★ same condition
SLC6A1 p.Arg479Ter Pathogenic ★★ same condition
SLC6A1 p.Gln106Arg Likely pathogenic ★★ same condition
SLC6A1 p.Gln534Ter Pathogenic ★★ 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/slc6a1-p-val125met (accessed [today's date]).

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