Is SETX p.Arg20His (c.59G>A) pathogenic?

SETX p.Arg20His (c.59G>A) is classified Benign/Likely benign in SETX (ClinVar, Multiple submitters, 16 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0686); Low-frequency (popmax 1.7%, sas); Associated with spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2.

What condition is associated with SETX p.Arg20His (c.59G>A)?

SETX p.Arg20His (c.59G>A) is associated with spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, amyotrophic lateral sclerosis type 4, hereditary spastic paraplegia (ClinVar).

How common is SETX p.Arg20His (c.59G>A) in the general population?

SETX p.Arg20His (c.59G>A) is low-frequency (popmax 1.7%, sas) (gnomAD).

What do computational predictors say about SETX p.Arg20His (c.59G>A)?

AlphaMissense predicts likely benign (score 0.0686) — an in-silico prediction, not a clinical call.

SETX p.Arg20His

Q: How is Spinocerebellar ataxia with axonal neuropathy type 2 inherited?

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

c.59G>A · rs79740039 · VCV242635

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 16 submitters

AlphaMissense

likely benign

0.0686 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.7%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Computational evidence

Protein change
AlphaMissense	0.0686	likely benign
REVEL	0.159	moderately benign-leaning
SaProt	LLR -7.70	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 0.1	GERP -2.8, phastCons 0.002
Regional constraint	o/e 0.97	unconstrained · MANE · 3,163 bp · p 0.74 · regional, not allelic
Overall
CADD	6.57	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 1.7% South Asian · 1,548/91,082 alleles

Filtering AF 1.63% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.6%

Overall 0.853% 13,762/1,614,102 alleles · low-frequency exomes 12,794/1,461,892 · genomes 968/152,210 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	1.7%	59
Ashkenazi Jewishnot grpmax-eligible	1.53%	65
Finnishnot grpmax-eligible	1.43%	70
Middle Eastern	1.04%	96
Remaining individualsnot grpmax-eligible	0.877%	114
European (non-Finnish)	0.839%	119
Admixed American	0.415%	241
Amishnot grpmax-eligible	0.219%	456
African / African-American	0.104%	961
East Asian	0.0111%	8,976

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.Arg20His
Coding: c.59G>A
MANE Select: NM_015046
dbSNP: rs79740039
Type: single nucleotide variant
Location: chr9:132349370 (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

spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: amyotrophic lateral sclerosis type 4 hereditary spastic paraplegia

For Spinocerebellar ataxia with axonal neuropathy type 2 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 1 000 000 (France)

Similar variants

SETX p.Arg20= Conflicting classifications of pathogenicity ★ same residue
SETX p.Arg20Cys Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg20his (accessed [today's date]).

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