Is SETX p.Lys1244= (c.3732A>G) pathogenic?

SETX p.Lys1244= (c.3732A>G) is classified Likely benign in SETX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-24). Very rare (popmax 0.00678%, nfe); Associated with amyotrophic lateral sclerosis type 4.

What condition is associated with SETX p.Lys1244= (c.3732A>G)?

SETX p.Lys1244= (c.3732A>G) is associated with amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

How common is SETX p.Lys1244= (c.3732A>G) in the general population?

SETX p.Lys1244= (c.3732A>G) is very rare (popmax 0.00678%, nfe) (gnomAD).

How is Amyotrophic lateral sclerosis type 4 inherited?

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

SETX p.Lys1244=

c.3732A>G · rs765897246 · VCV2924927

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00678%, nfe)

Conditions

amyotrophic lateral sclerosis type 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.16	GERP -3, phastCons 0.51
Overall
CADD	0.778	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00678% European (non-Finnish) · 80/1,180,042 alleles

Filtering AF 0.00554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.00527% 85/1,614,092 alleles · very rare exomes 84/1,461,886 · genomes 1/152,206 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00678%	14,751
Admixed American	0.005%	19,999
East Asian	0.00445%	22,449

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: SETX
Protein: p.Lys1244=
Coding: c.3732A>G
MANE Select: NM_015046
dbSNP: rs765897246
Type: single nucleotide variant
Location: chr9:132327866 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 1244: the 'disordered' region

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

Disease context

amyotrophic lateral sclerosis type 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

For Amyotrophic lateral sclerosis type 4 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Childhood

Similar variants

SETX p.Arg111Ter Pathogenic ★★ same condition
SETX p.Arg1363Ter Pathogenic ★★ same condition
SETX p.Arg1606Ter Pathogenic ★★ same condition
SETX p.Arg1778Ter Pathogenic/Likely pathogenic ★★ same condition
SETX p.Arg2098Ter Pathogenic ★★ same condition
SETX p.Arg332Trp Pathogenic/Likely pathogenic ★★ same condition
SETX p.Arg778Ter Pathogenic/Likely pathogenic ★★ same condition
SETX p.Gln1695Ter Pathogenic/Likely 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/setx-p-lys1244 (accessed [today's date]).

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