Is SETX p.Val2579Ile (c.7735G>A) pathogenic?

SETX p.Val2579Ile (c.7735G>A) is classified Conflicting classifications of pathogenicity in SETX (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-03-24). AlphaMissense: likely benign (0.0804); Ultra-rare (popmax 0.0103%, nfe); Associated with Inborn genetic diseases.

How common is SETX p.Val2579Ile (c.7735G>A) in the general population?

SETX p.Val2579Ile (c.7735G>A) is ultra-rare (popmax 0.0103%, nfe) (gnomAD).

What do computational predictors say about SETX p.Val2579Ile (c.7735G>A)?

AlphaMissense predicts likely benign (score 0.0804) — an in-silico prediction, not a clinical call.

SETX p.Val2579Ile

Q: What condition is associated with SETX p.Val2579Ile (c.7735G>A)?

SETX p.Val2579Ile (c.7735G>A) is associated with Inborn genetic diseases, amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

c.7735G>A · rs144121978 · VCV365341

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0804 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0804	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -7.38	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 -4.3	GERP -2.2
Regional constraint	o/e 1.05	unconstrained · MANE · 671 bp · p 0.36 · regional, not allelic
Overall
CADD	0.026	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 0.0103% European (non-Finnish) · 121/1,179,982 alleles

Filtering AF 0.00876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0082%

Overall 0.00793% 128/1,613,874 alleles · ultra-rare exomes 118/1,461,728 · genomes 10/152,146 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0103%	9,752
African / African-American	0.00534%	18,723
Admixed American	0.00333%	30,000
Remaining individualsnot grpmax-eligible	0.0016%	62,476

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.Val2579Ile
Coding: c.7735G>A
MANE Select: NM_015046
dbSNP: rs144121978
Type: single nucleotide variant
Location: chr9:132264538 (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.Val2579Gly Uncertain significance ★ ⚠ same residue
SETX p.Val2579Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
SETX p.Val2579= Likely benign ★★ same residue
SETX p.Val2579Ala Uncertain significance ★ ⚠ 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

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-val2579ile (accessed [today's date]).

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