Is SETX p.Asp1937= (c.5811T>C) pathogenic?

SETX p.Asp1937= (c.5811T>C) is classified Benign/Likely benign in SETX (ClinVar, Multiple submitters, 18 submitters; last evaluated 2026-02-04). Common (popmax 70.2%, eas) — too common for a highly-penetrant pathogenic allele; Associated with amyotrophic lateral sclerosis type 4.

What condition is associated with SETX p.Asp1937= (c.5811T>C)?

SETX p.Asp1937= (c.5811T>C) is associated with amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

How is Amyotrophic lateral sclerosis type 4 inherited?

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

SETX p.Asp1937=

Q: How common is SETX p.Asp1937= (c.5811T>C) in the general population?

SETX p.Asp1937= (c.5811T>C) is common (popmax 70.2%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.5811T>C · rs2296869 · VCV95667

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 18 submitters

gnomAD v4.1

Common

common (popmax 70.2%, eas) — too common for a highly-penetrant pathogenic allele

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -3.5, phastCons 1
Overall
CADD	6.95	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 70.2% East Asian · 31,464/44,834 alleles

Filtering AF 69.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 69.3%

Overall 21% 338,424/1,612,012 alleles · common exomes 290,173/1,460,014 · genomes 48,251/151,998 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	70.2%	1
African / African-American	62.3%	2
South Asian	36.2%	3
Middle Eastern	34%	3
Ashkenazi Jewishnot grpmax-eligible	25.5%	4
Remaining individualsnot grpmax-eligible	24.6%	4
Admixed American	20.8%	5
Finnishnot grpmax-eligible	16.9%	6
European (non-Finnish)	15.2%	7
Amishnot grpmax-eligible	13.9%	7

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.Asp1937=
Coding: c.5811T>C
MANE Select: NM_015046
dbSNP: rs2296869
Type: single nucleotide variant
Location: chr9:132297025 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 1937: the upf1-type sf1b helicase atp-binding domain

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.Asp1937Tyr Uncertain significance ★★ same residue
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

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-asp1937 (accessed [today's date]).

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