Is SETX p.Pro2213Ala (c.6637C>G) pathogenic?

SETX p.Pro2213Ala (c.6637C>G) is classified Uncertain significance in SETX (ClinVar, Single submitter, 1 submitter; last evaluated 2019-04-23). AlphaMissense: ambiguous (0.5056); Very rare (popmax 0.00017%, nfe); Associated with spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2.

What condition is associated with SETX p.Pro2213Ala (c.6637C>G)?

SETX p.Pro2213Ala (c.6637C>G) is associated with spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

How common is SETX p.Pro2213Ala (c.6637C>G) in the general population?

SETX p.Pro2213Ala (c.6637C>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about SETX p.Pro2213Ala (c.6637C>G)?

AlphaMissense predicts ambiguous (score 0.5056) — an in-silico prediction, not a clinical call.

SETX p.Pro2213Ala

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.6637C>G · rs1843502057 · VCV930621

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5056 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Computational evidence

Protein change
AlphaMissense	0.5056	ambiguous
REVEL	0.697	pathogenic-leaning
SaProt	LLR -5.17	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 32 kb · p 3e-13 · regional, not allelic
Overall
CADD	27.1	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 0.00017% European (non-Finnish) · 2/1,179,070 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,054 alleles · very rare exomes 2/1,460,786 · genomes 0/152,268 · 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.Pro2213Ala
Coding: c.6637C>G
MANE Select: NM_015046
dbSNP: rs1843502057
Type: single nucleotide variant
Location: chr9:132281484 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 2213: the upf1-type sf1b helicase atp-binding domain; a UniProt-annotated variant site (in scan2)

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

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.Pro2213Leu Uncertain significance ★ ⚠ same residue
SETX p.Pro2213= Benign ★ same residue
SETX p.Pro2213Gln Uncertain significance ★ ⚠ 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.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-pro2213ala (accessed [today's date]).

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