Is SETX p.His1049= (c.3147C>T) pathogenic?

SETX p.His1049= (c.3147C>T) is classified Benign/Likely benign in SETX (ClinVar, Multiple submitters, 16 submitters; last evaluated 2026-02-04). Common (popmax 25.5%, eas) — too common for a highly-penetrant pathogenic allele; Associated with amyotrophic lateral sclerosis type 4.

What condition is associated with SETX p.His1049= (c.3147C>T)?

SETX p.His1049= (c.3147C>T) 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.His1049=

Q: How common is SETX p.His1049= (c.3147C>T) in the general population?

SETX p.His1049= (c.3147C>T) is common (popmax 25.5%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3147C>T · rs3739921 · VCV193716

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 16 submitters

gnomAD v4.1

Common

common (popmax 25.5%, 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 -1.4	GERP -3.2
Overall
CADD	0.374	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 25.5% East Asian · 11,420/44,852 alleles

Filtering AF 25.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 24.9%

Overall 9.14% 147,391/1,613,326 alleles · common exomes 134,961/1,461,300 · genomes 12,430/152,026 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	25.5%	4
South Asian	20.1%	5
Middle Eastern	17.6%	6
Ashkenazi Jewishnot grpmax-eligible	13%	8
Remaining individualsnot grpmax-eligible	10.2%	10
Admixed American	8.77%	11
Amishnot grpmax-eligible	8.04%	12
European (non-Finnish)	7.87%	13
Finnishnot grpmax-eligible	7.83%	13
African / African-American	4.33%	23

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.His1049=
Coding: c.3147C>T
MANE Select: NM_015046
dbSNP: rs3739921
Type: single nucleotide variant
Location: chr9:132328451 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93

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-his1049 (accessed [today's date]).

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