Is SETX p.Ile1386Val (c.4156A>G) pathogenic?

SETX p.Ile1386Val (c.4156A>G) is classified Benign in SETX (ClinVar, Multiple submitters, 18 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0721); Common (popmax 84.9%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2.

What do computational predictors say about SETX p.Ile1386Val (c.4156A>G)?

AlphaMissense predicts likely benign (score 0.0721) — an in-silico prediction, not a clinical call.

SETX p.Ile1386Val

Q: What condition is associated with SETX p.Ile1386Val (c.4156A>G)?

SETX p.Ile1386Val (c.4156A>G) is associated with spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, amyotrophic lateral sclerosis type 4 (ClinVar).

Q: How common is SETX p.Ile1386Val (c.4156A>G) in the general population?

SETX p.Ile1386Val (c.4156A>G) is common (popmax 84.9%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.4156A>G · rs543573 · VCV95663

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 18 submitters

AlphaMissense

likely benign

0.0721 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 84.9%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Computational evidence

Protein change
AlphaMissense	0.0721	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -5.95	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 -6.3	GERP -3.6
Regional constraint	o/e 1.13	unconstrained · MANE · 3,399 bp · p 2.4e-06 · regional, not allelic
Overall
CADD	0.003	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 84.9% European (non-Finnish) · 1,002,265/1,179,970 alleles

Filtering AF 84.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 84.7%

Overall 79.1% 1,276,412/1,613,932 alleles · common exomes 1,172,476/1,461,760 · genomes 103,936/152,172 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	86.1%	1
European (non-Finnish)grpmax	84.9%	1
Finnishnot grpmax-eligible	83.2%	1
Admixed American	79.2%	1
Remaining individualsnot grpmax-eligible	75.5%	1
Ashkenazi Jewishnot grpmax-eligible	74.5%	1
Middle Eastern	66.3%	2
South Asian	63.7%	2
African / African-American	37.7%	3
East Asian	29.2%	3

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile1386Val
Coding: c.4156A>G
MANE Select: NM_015046
dbSNP: rs543573
Type: single nucleotide variant
Location: chr9:132327442 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 1386: a UniProt-annotated variant site (in)

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

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.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
SETX p.Gln1695Ter 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-ile1386val (accessed [today's date]).

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