Is SETX p.Val656= (c.1968A>G) pathogenic?

SETX p.Val656= (c.1968A>G) is classified Benign/Likely benign in SETX (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-19). Low-frequency (popmax 2.09%, afr); Associated with Inborn genetic diseases.

How common is SETX p.Val656= (c.1968A>G) in the general population?

SETX p.Val656= (c.1968A>G) is low-frequency (popmax 2.09%, afr) (gnomAD).

SETX p.Val656=

Q: What condition is associated with SETX p.Val656= (c.1968A>G)?

SETX p.Val656= (c.1968A>G) is associated with Inborn genetic diseases, amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

c.1968A>G · rs113997459 · VCV536399

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.09%, afr)

Conditions

Inborn genetic diseases

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 -0.42	GERP -3.6
Overall
CADD	0.653	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.09% African / African-American · 1,567/75,014 alleles

Filtering AF 2% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.97%

Overall 0.112% 1,810/1,613,834 alleles · low-frequency exomes 906/1,461,466 · genomes 904/152,368 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.09%	48
Admixed American	0.18%	555
Remaining individualsnot grpmax-eligible	0.155%	644
Middle Eastern	0.033%	3,031
South Asian	0.0033%	30,341
European (non-Finnish)	0.0028%	35,757

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.Val656=
Coding: c.1968A>G
MANE Select: NM_015046
dbSNP: rs113997459
Type: single nucleotide variant
Location: chr9:132329630 (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

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 hereditary spastic paraplegia

Similar variants

SETX p.Val656Ile 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-val656 (accessed [today's date]).

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