Is SETX p.Lys2018Glu (c.6052A>G) pathogenic?

SETX p.Lys2018Glu (c.6052A>G) is classified Uncertain significance in SETX (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.9075); Very rare (popmax 0.000169%, nfe); Associated with hereditary motor neuron disease.

What condition is associated with SETX p.Lys2018Glu (c.6052A>G)?

SETX p.Lys2018Glu (c.6052A>G) is associated with hereditary motor neuron disease (ClinVar).

How common is SETX p.Lys2018Glu (c.6052A>G) in the general population?

SETX p.Lys2018Glu (c.6052A>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about SETX p.Lys2018Glu (c.6052A>G)?

AlphaMissense predicts likely pathogenic (score 0.9075) — an in-silico prediction, not a clinical call.

SETX p.Lys2018Glu

c.6052A>G · rs1554811438 · VCV637405

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9075 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary motor neuron disease

Computational evidence

Protein change
AlphaMissense	0.9075	likely pathogenic · top 10% in SETX
REVEL	0.788	moderately pathogenic-leaning
SaProt	LLR -8.45	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 32 kb · p 3e-13 · regional, not allelic
Overall
CADD	27.2	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 0.000169% European (non-Finnish) · 2/1,179,970 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,130 alleles · very rare exomes 2/1,461,788 · genomes 0/152,342 · joint denominator

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.Lys2018Glu
Coding: c.6052A>G
MANE Select: NM_015046
dbSNP: rs1554811438
Type: single nucleotide variant
Location: chr9:132295926 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 2018: the upf1-type sf1b helicase atp-binding domain

Full SETX gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary motor neuron disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETX p.Arg111Ter Pathogenic ★★ same type
SETX p.Arg1363Ter Pathogenic ★★ same type
SETX p.Arg1606Ter Pathogenic ★★ same type
SETX p.Arg1778Ter Pathogenic/Likely pathogenic ★★ same type
SETX p.Arg2098Ter Pathogenic ★★ same type
SETX p.Arg332Trp Pathogenic/Likely pathogenic ★★ same type
SETX p.Arg778Ter Pathogenic/Likely pathogenic ★★ same type
SETX p.Gln1695Ter Pathogenic/Likely pathogenic ★★ same type

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-lys2018glu (accessed [today's date]).

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