Is SETX p.Ser2142fs (c.6422dup) pathogenic?

SETX p.Ser2142fs (c.6422dup) is classified Pathogenic/Likely pathogenic in SETX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-20). Very rare (popmax 0.00878%, sas); Associated with amyotrophic lateral sclerosis type 4.

What condition is associated with SETX p.Ser2142fs (c.6422dup)?

SETX p.Ser2142fs (c.6422dup) is associated with amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

How common is SETX p.Ser2142fs (c.6422dup) in the general population?

SETX p.Ser2142fs (c.6422dup) is very rare (popmax 0.00878%, 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.Ser2142fs

c.6422dup · rs768349691 · VCV2159483

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00878%, 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	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 19 of 26
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.8	GERP 1.5, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00878% South Asian · 8/91,078 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.000496% 8/1,614,194 alleles · very rare exomes 8/1,461,882 · genomes 0/152,312 · joint denominator

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.Ser2142fs
Coding: c.6422dup
MANE Select: NM_015046
dbSNP: rs768349691
Type: Duplication
Location: chr9:132283387 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 2142: 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.Asp1742fs Pathogenic/Likely pathogenic ★★ same condition
SETX p.Leu1750fs Pathogenic/Likely pathogenic ★★ same condition
SETX p.Phe2300fs Pathogenic/Likely pathogenic ★★ same condition
SETX p.Glu2548Ter Uncertain significance ★★ same condition
SETX c.1010+4_1010+7dup Likely benign ★★ same condition
SETX c.5781+12dup Benign/Likely benign ★★ same condition
SETX c.6843-16dup Benign/Likely benign ★★ same condition
SETX c.6843-6_6843-5dup Benign/Likely benign ★★ 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-ser2142fs (accessed [today's date]).

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