Is SETX p.Ile81Val (c.241A>G) pathogenic?

SETX p.Ile81Val (c.241A>G) is classified Conflicting classifications of pathogenicity in SETX (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-07-11). AlphaMissense: likely benign (0.0796); Very rare (popmax 0.005%, amr); Associated with Inborn genetic diseases.

How common is SETX p.Ile81Val (c.241A>G) in the general population?

SETX p.Ile81Val (c.241A>G) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about SETX p.Ile81Val (c.241A>G)?

AlphaMissense predicts likely benign (score 0.0796) — an in-silico prediction, not a clinical call.

SETX p.Ile81Val

Q: What condition is associated with SETX p.Ile81Val (c.241A>G)?

SETX p.Ile81Val (c.241A>G) is associated with Inborn genetic diseases, amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

c.241A>G · rs371166895 · VCV1790987

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0796 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0796	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -5.79	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 0.55	GERP -0.65, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 3,163 bp · p 0.74 · regional, not allelic
Overall
CADD	14.59	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 0.005% Admixed American · 3/60,018 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00217% 35/1,613,962 alleles · very rare exomes 32/1,461,618 · genomes 3/152,344 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,006
African / African-American	0.00266%	37,533
European (non-Finnish)	0.00246%	40,685
Remaining individualsnot grpmax-eligible	0.0016%	62,500

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.Ile81Val
Coding: c.241A>G
MANE Select: NM_015046
dbSNP: rs371166895
Type: single nucleotide variant
Location: chr9:132346408 (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

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-ile81val (accessed [today's date]).

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