Is SETX p.Ser2117= (c.6351C>T) pathogenic?

SETX p.Ser2117= (c.6351C>T) is classified Likely benign in SETX (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-23). Rare (popmax 0.182%, mid); Associated with amyotrophic lateral sclerosis type 4.

What condition is associated with SETX p.Ser2117= (c.6351C>T)?

SETX p.Ser2117= (c.6351C>T) is associated with amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

How common is SETX p.Ser2117= (c.6351C>T) in the general population?

SETX p.Ser2117= (c.6351C>T) is rare (popmax 0.182%, mid) (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.Ser2117=

c.6351C>T · rs200269892 · VCV704754

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.182%, mid)

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 -0.44	GERP -2.9
Overall
CADD	2.434	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.182% Middle Eastern · 11/6,054 alleles

Filtering AF 0.102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0788%

Overall 0.00527% 85/1,613,150 alleles · rare exomes 83/1,461,344 · genomes 2/151,806 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.182%	550
European (non-Finnish)	0.00551%	18,149
Admixed American	0.005%	19,988
Remaining individualsnot grpmax-eligible	0.0048%	20,832
South Asian	0.0033%	30,344

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.Ser2117=
Coding: c.6351C>T
MANE Select: NM_015046
dbSNP: rs200269892
Type: single nucleotide variant
Location: chr9:132286468 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 2117: 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.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-ser2117 (accessed [today's date]).

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