Is SETX p.Arg2098Ter (c.6292C>T) pathogenic?

SETX p.Arg2098Ter (c.6292C>T) is classified Pathogenic in SETX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2015-12-22). Very rare (popmax 0.0022%, sas); Associated with amyotrophic lateral sclerosis type 4.

What condition is associated with SETX p.Arg2098Ter (c.6292C>T)?

SETX p.Arg2098Ter (c.6292C>T) is associated with amyotrophic lateral sclerosis type 4 (ClinVar).

How common is SETX p.Arg2098Ter (c.6292C>T) in the general population?

SETX p.Arg2098Ter (c.6292C>T) is very rare (popmax 0.0022%, sas) (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.Arg2098Ter

c.6292C>T · rs770684782 · VCV586555

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

amyotrophic lateral sclerosis type 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 17 of 26
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.7, phastCons 1
Overall
CADD	47.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,078 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000248% 4/1,614,130 alleles · very rare exomes 4/1,461,812 · genomes 0/152,318 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,539
European (non-Finnish)	0.000169%	589,995

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.Arg2098Ter
Coding: c.6292C>T
MANE Select: NM_015046
dbSNP: rs770684782
Type: single nucleotide variant
Location: chr9:132288268 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 2098: 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

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.Gln1695Ter Pathogenic/Likely pathogenic ★★ same condition
SETX p.Gln1774Ter Pathogenic/Likely pathogenic ★★ same condition
SETX p.Leu389Ser Pathogenic ★★ ⚠ same condition
SETX p.Ser1618Ter Pathogenic ★★ same condition
SETX p.Thr3Ile 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-arg2098ter (accessed [today's date]).

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