Is SETX p.Lys1327= (c.3981A>G) pathogenic?

SETX p.Lys1327= (c.3981A>G) is classified Uncertain significance in SETX (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-12). Very rare (popmax 0.000847%, nfe); Associated with hereditary spastic paraplegia.

What condition is associated with SETX p.Lys1327= (c.3981A>G)?

SETX p.Lys1327= (c.3981A>G) is associated with hereditary spastic paraplegia (ClinVar).

How common is SETX p.Lys1327= (c.3981A>G) in the general population?

SETX p.Lys1327= (c.3981A>G) is very rare (popmax 0.000847%, nfe) (gnomAD).

SETX p.Lys1327=

c.3981A>G · rs1308547907 · VCV1344018

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Conditions

hereditary spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.7	GERP -1.9
Overall
CADD	3.87	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000847% European (non-Finnish) · 10/1,179,986 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.00062% 10/1,614,004 alleles · very rare exomes 10/1,461,710 · genomes 0/152,294 · 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.Lys1327=
Coding: c.3981A>G
MANE Select: NM_015046
dbSNP: rs1308547907
Type: single nucleotide variant
Location: chr9:132327617 (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

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

Similar variants

SETX p.Gly1011Arg Uncertain significance ★★ ⚠ same condition
SETX p.Ala1112= Benign/Likely benign ★★ same condition
SETX p.Ala1782= Benign/Likely benign ★★ same condition
SETX p.Arg20His Benign/Likely benign ★★ same condition
SETX p.Asn603Asp Benign/Likely benign ★★ same condition
SETX p.Asp2372Asn Benign/Likely benign ★★ ⚠ same condition
SETX p.Cys1554Gly Benign/Likely benign ★★ ⚠ same condition
SETX p.Gln653Lys Benign/Likely benign ★★ 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-lys1327 (accessed [today's date]).

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