Is SETX p.Pro2213= (c.6639G>A) pathogenic?

SETX p.Pro2213= (c.6639G>A) is classified Benign in SETX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-24). Ultra-rare (popmax 0.0165%, sas); Associated with amyotrophic lateral sclerosis type 4.

What condition is associated with SETX p.Pro2213= (c.6639G>A)?

SETX p.Pro2213= (c.6639G>A) is associated with amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

How common is SETX p.Pro2213= (c.6639G>A) in the general population?

SETX p.Pro2213= (c.6639G>A) is ultra-rare (popmax 0.0165%, 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.Pro2213=

c.6639G>A · VCV3758214

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, sas)

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 1.1	GERP -2.6, phastCons 1
Overall
CADD	10.98	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% South Asian · 15/91,032 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00811%

Overall 0.00118% 19/1,612,530 alleles · ultra-rare exomes 17/1,460,326 · genomes 2/152,204 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0165%	6,069
Remaining individualsnot grpmax-eligible	0.0032%	31,221
East Asian	0.00223%	44,864
European (non-Finnish)	8.48e-05%	1,178,655

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.Pro2213=
Coding: c.6639G>A
MANE Select: NM_015046
Type: single nucleotide variant
Location: chr9:132281482 (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

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.Pro2213Ala Uncertain significance ★ ⚠ same residue
SETX p.Pro2213Leu Uncertain significance ★ ⚠ 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.Arg2098Ter 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-pro2213 (accessed [today's date]).

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