Is SETX p.Ala2079Val (c.6236C>T) pathogenic?

SETX p.Ala2079Val (c.6236C>T) is classified Conflicting classifications of pathogenicity in SETX (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-08-02). AlphaMissense: likely benign (0.1035); Very rare (popmax 0.00401%, afr); Associated with amyotrophic lateral sclerosis type 4.

What condition is associated with SETX p.Ala2079Val (c.6236C>T)?

SETX p.Ala2079Val (c.6236C>T) is associated with amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

How common is SETX p.Ala2079Val (c.6236C>T) in the general population?

SETX p.Ala2079Val (c.6236C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

How is Amyotrophic lateral sclerosis type 4 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SETX p.Ala2079Val (c.6236C>T)?

AlphaMissense predicts likely benign (score 0.1035) — an in-silico prediction, not a clinical call.

SETX p.Ala2079Val

c.6236C>T · rs767898864 · VCV2933815

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1035 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyotrophic lateral sclerosis type 4

Computational evidence

Protein change
AlphaMissense	0.1035	likely benign
REVEL	0.284	benign-leaning
SaProt	LLR -7.76	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.61	acceptor gain · deltas
Pangolin	Δ0.45	gain · loss 0.37 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6.2	GERP 0.62, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 32 kb · p 3e-13 · regional, not allelic
Overall
CADD	27.7	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 0.00401% African / African-American · 3/74,862 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000372% 6/1,613,536 alleles · very rare exomes 4/1,461,496 · genomes 2/152,040 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,954
Remaining individualsnot grpmax-eligible	0.0016%	62,472
European (non-Finnish)	0.00017%	589,845

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.Ala2079Val
Coding: c.6236C>T
MANE Select: NM_015046
dbSNP: rs767898864
Type: single nucleotide variant
Location: chr9:132288324 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 2079: the upf1-type sf1b helicase atp-binding domain

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.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-ala2079val (accessed [today's date]).

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