Is SETX p.Ser512Cys (c.1535C>G) pathogenic?

SETX p.Ser512Cys (c.1535C>G) is classified Benign in SETX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-12). AlphaMissense: likely benign (0.0762); Ultra-rare (popmax 0.0133%, amr); Associated with amyotrophic lateral sclerosis type 4.

What condition is associated with SETX p.Ser512Cys (c.1535C>G)?

SETX p.Ser512Cys (c.1535C>G) is associated with amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

How common is SETX p.Ser512Cys (c.1535C>G) in the general population?

SETX p.Ser512Cys (c.1535C>G) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

How is Amyotrophic lateral sclerosis type 4 inherited?

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

What do computational predictors say about SETX p.Ser512Cys (c.1535C>G)?

AlphaMissense predicts likely benign (score 0.0762) — an in-silico prediction, not a clinical call.

SETX p.Ser512Cys

c.1535C>G · rs533943279 · VCV2924405

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0762 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyotrophic lateral sclerosis type 4

Computational evidence

Protein change
AlphaMissense	0.0762	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	LLR -9.15	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 522 bp · p 0.2 · regional, not allelic
Overall
CADD	19.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% Admixed American · 8/60,028 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.000929% 15/1,614,198 alleles · ultra-rare exomes 14/1,461,870 · genomes 1/152,328 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,504
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	0.000508%	196,670

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.Ser512Cys
Coding: c.1535C>G
MANE Select: NM_015046
dbSNP: rs533943279
Type: single nucleotide variant
Location: chr9:132330063 (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.Ser512= Likely benign ★ 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-ser512cys (accessed [today's date]).

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