Is SETX p.Pro2570Ser (c.7708C>T) pathogenic?

SETX p.Pro2570Ser (c.7708C>T) is classified Conflicting classifications of pathogenicity in SETX (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-04). AlphaMissense: likely benign (0.0754); Very rare (popmax 0.00801%, afr); Associated with Inborn genetic diseases.

How common is SETX p.Pro2570Ser (c.7708C>T) in the general population?

SETX p.Pro2570Ser (c.7708C>T) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about SETX p.Pro2570Ser (c.7708C>T)?

AlphaMissense predicts likely benign (score 0.0754) — an in-silico prediction, not a clinical call.

SETX p.Pro2570Ser

Q: What condition is associated with SETX p.Pro2570Ser (c.7708C>T)?

SETX p.Pro2570Ser (c.7708C>T) is associated with Inborn genetic diseases, amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

c.7708C>T · rs1240232139 · VCV536379

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0754 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0754	likely benign
REVEL	0.18	moderately benign-leaning
SaProt	LLR -5.34	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 0.59	GERP -3.3
Regional constraint	o/e 1.05	unconstrained · MANE · 671 bp · p 0.36 · regional, not allelic
Overall
CADD	6.973	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 0.00801% African / African-American · 6/74,920 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000558% 9/1,614,050 alleles · very rare exomes 7/1,461,856 · genomes 2/152,194 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,487
European (non-Finnish)	0.000254%	393,351

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.Pro2570Ser
Coding: c.7708C>T
MANE Select: NM_015046
dbSNP: rs1240232139
Type: single nucleotide variant
Location: chr9:132264565 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 2570: the 'disordered' region

Full SETX gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: amyotrophic lateral sclerosis type 4 spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Similar variants

SETX p.Pro2570Leu 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
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-pro2570ser (accessed [today's date]).

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