Is SETX p.Ala488Thr (c.1462G>A) pathogenic?

SETX p.Ala488Thr (c.1462G>A) is classified Uncertain significance in SETX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-02-20). AlphaMissense: likely benign (0.194); Very rare (popmax 0.00357%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SETX p.Ala488Thr (c.1462G>A)?

SETX p.Ala488Thr (c.1462G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SETX p.Ala488Thr (c.1462G>A) in the general population?

SETX p.Ala488Thr (c.1462G>A) is very rare (popmax 0.00357%, nfe) (gnomAD).

What do computational predictors say about SETX p.Ala488Thr (c.1462G>A)?

AlphaMissense predicts likely benign (score 0.194) — an in-silico prediction, not a clinical call.

SETX p.Ala488Thr

c.1462G>A · rs374334031 · VCV1773187

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.194 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00357%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.194	likely benign
REVEL	0.433	indeterminate
SaProt	LLR -2.88	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 522 bp · p 0.2 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00357% European (non-Finnish) · 42/1,177,928 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00237%

Overall 0.00273% 44/1,611,498 alleles · very rare exomes 41/1,459,250 · genomes 3/152,248 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00357%	28,046
Remaining individualsnot grpmax-eligible	0.00321%	31,193

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.Ala488Thr
Coding: c.1462G>A
MANE Select: NM_015046
dbSNP: rs374334031
Type: single nucleotide variant
Location: chr9:132330136 (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

Similar variants

SETX p.Ala488= Likely benign ★ same residue
SETX p.Arg1363Ter Pathogenic ★★ same condition
SETX p.Ala1945Val Uncertain significance ★★ ⚠ same condition
SETX p.Ala2596Pro Uncertain significance ★★ ⚠ same condition
SETX p.Arg1214Ser Uncertain significance ★★ ⚠ same condition
SETX p.Arg1302Leu Uncertain significance ★★ same condition
SETX p.Arg1846His Uncertain significance ★★ ⚠ same condition
SETX p.Arg1846Leu Uncertain significance ★★ ⚠ 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-ala488thr (accessed [today's date]).

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