SIGMAR1

Chr 9AR

sigma non-opioid intracellular receptor 1

Also known as: ALS16, DSMA2, HMNR2, OPRS1, SIG-1R, SR-BP, SR-BP1, SRBP

NCBI Gene: 10280ENSG00000147955UniProt: Q99720

This gene encodes a receptor protein that interacts with a variety of psychotomimetic drugs, including cocaine and amphetamines. The receptor is believed to play an important role in the cellular functions of various tissues associated with the endocrine, immune, and nervous systems. As indicated by its previous name, opioid receptor sigma 1 (OPRS1), the product of this gene was erroneously thought to function as an opioid receptor; it is now thought to be a non-opioid receptor. Mutations in this gene has been associated with juvenile amyotrophic lateral sclerosis 16. Alternative splicing of this gene results in transcript variants encoding distinct isoforms. [provided by RefSeq, Aug 2013]

Primary Disease Associations & Inheritance

?Amyotrophic lateral sclerosis 16, juvenileMIM #614373
AR
?Neuronopathy, distal hereditary motor, autosomal recessive 2MIM #605726
AR
309
ClinVar variants
97
Pathogenic / LP
0.17
pLI score
1
Active trials
Clinical Summary— SIGMAR1
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.28) despite low pLI — interpret in context.
📋
ClinVar Variants
97 Pathogenic / Likely Pathogenic· 104 VUS of 309 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.74LOEUF
pLI 0.168
Z-score 2.15
OE 0.28 (0.13–0.74)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.46Z-score
OE missense 0.64 (0.54–0.77)
85 obs / 132.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.28 (0.13–0.74)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.64 (0.54–0.77)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.89
0≤1.21.6
LoF obs/exp: 3 / 10.5Missense obs/exp: 85 / 132.3Syn Z: 0.66

ClinVar Variant Classifications

309 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic76
Likely Pathogenic21
VUS104
Likely Benign84
Benign13
Conflicting3
76
Pathogenic
21
Likely Pathogenic
104
VUS
84
Likely Benign
13
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
8
1
65
2
76
Likely Pathogenic
9
4
8
0
21
VUS
2
86
15
1
104
Likely Benign
1
16
25
42
84
Benign
0
1
9
3
13
Conflicting
—3
Total2010812248301

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

SIGMAR1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Amyotrophic lateral sclerosis 16, juvenile

MIM #614373

Molecular basis of disorder known

Autosomal recessive

?Neuronopathy, distal hereditary motor, autosomal recessive 2

MIM #605726

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Distal hereditary motor neuropathies.
Tazir M et al.·Rev Neurol (Paris)
2024Review
Blarcamesine for the treatment of Early Alzheimer's Disease: Results from the ANAVEX2-73-AD-004 Phase IIB/III trial.
Macfarlane S et al.·J Prev Alzheimers Dis
2025Clinical trial
SIGMAR1 Confers Innate Resilience against Neurodegeneration.
Couly S et al.·Int J Mol Sci
2023Review
Environmental Control of Astrocyte Pathogenic Activities in CNS Inflammation.
Wheeler MA et al.·Cell
2019
SIGMAR1 screened by a GPCR-related classifier regulates endoplasmic reticulum stress in bladder cancer.
Zhuang J et al.·J Transl Med
2025
Genetic and clinical landscape of Chinese frontotemporal dementia: dominance of TBK1 and OPTN mutations.
Nan H et al.·Alzheimers Res Ther
2024
SIGMAR1 mutation associated with autosomal recessive Silver-like syndrome.
Horga A et al.·Neurology
2016Review
The role of SIGMAR1 gene mutation and mitochondrial dysfunction in amyotrophic lateral sclerosis.
Fukunaga K et al.·J Pharmacol Sci
2015Review
Genetic and Neuroimaging Analysis of SIGMAR1 for Frontotemporal Dementia.
Che XQ et al.·J Alzheimers Dis
2023
SARS-CoV-2 NSP6 reduces autophagosome size and affects viral replication via sigma-1 receptor.
Zhang C et al.·J Virol
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
SIRT3-mediated mitophagy by deacetylating ATP5F1A involved in the protective effects of SIGMAR1/Sigma-1 receptor against ferroptosis and microvascular hyperpermeability in lipopolysaccharide-induced acute lung injury.
Gao F et al.·Autophagy
2026
A Novel YTHDF2/SIGMAR1 Axis in Astrocytes Regulates Neuroinflammation and Cognitive Impairment in Diabetic Encephalopathy.
Xu F et al.·Inflammation
2026🔓 Open Access
SigmaR1 is an auxiliary translocon factor with lipid-binding activity that regulates protein and lipid droplet homeostasis.
Hu X et al.·Nat Commun
2025🔓 Open Access
SIGMAR1 Drives the Development of Neuropathic Pain by Promoting AMPA Receptor Membrane Trafficking Through Interacting with NPTX1 in Male Mice.
Ren J et al.·Neurosci Bull
2025
SIGMAR1 gene-related neuromuscular disorders - what do we know?
Kalita M et al.·Neurol Neurochir Pol
2026
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Schizophrenia

A Study of ANAVEX3-71 in Adults With Schizophrenia

ACTIVE NOT RECRUITING
NCT06245213Phase PHASE2Anavex Life Sciences Corp.Started 2024-03-15
ANAVEX3-71 oral capsulesPlacebo oral capsules

External Resources

Links to major genomics databases and tools