SQSTM1

Chr 5ADAR

sequestosome 1

NCBI Gene: 8878 ENSG00000161011 UniProt: Q13501 OMIM: 601530

This gene encodes a multifunctional scaffolding protein that binds ubiquitin, regulates NF-kB signaling pathway activation, and functions in autophagy. Mutations cause autosomal dominant frontotemporal dementia and/or amyotrophic lateral sclerosis, distal myopathy with rimmed vacuoles, and Paget disease of bone, as well as autosomal recessive childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy. The pathogenic mechanism involves disrupted protein aggregation clearance and impaired autophagy processes.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Molecular adapter required for selective macroautophagy (aggrephagy) by acting as a bridge between polyubiquitinated proteins and autophagosomes (PubMed:15340068, PubMed:15953362, PubMed:16286508, PubMed:17580304, PubMed:20168092, PubMed:22017874, PubMed:22622177, PubMed:24128730, PubMed:28404643, PubMed:29343546, PubMed:29507397, PubMed:31857589, PubMed:33509017, PubMed:34471133, PubMed:34893540, PubMed:35831301, PubMed:37306101, PubMed:37802024, PubMed:40542578). Promotes the recruitment of ubiquitinated cargo proteins to autophagosomes via multiple domains that bridge proteins and organelles in different steps (PubMed:16286508, PubMed:20168092, PubMed:22622177, PubMed:24128730, PubMed:28404643, PubMed:29343546, PubMed:29507397, PubMed:34893540, PubMed:37802024). SQSTM1 first mediates the assembly and removal of ubiquitinated proteins by undergoing liquid-liquid phase separation upon binding to ubiquitinated proteins via its UBA domain, leading to the formation of insoluble cytoplasmic inclusions, known as p62 bodies (PubMed:15911346, PubMed:20168092, PubMed:22017874, PubMed:24128730, PubMed:29343546, PubMed:29507397, PubMed:31857589, PubMed:37802024). SQSTM1 then interacts with ATG8 family proteins on autophagosomes via its LIR motif, leading to p62 body recruitment to autophagosomes, followed by autophagic clearance of ubiquitinated proteins (PubMed:16286508, PubMed:17580304, PubMed:20168092, PubMed:22622177, PubMed:24128730, PubMed:28404643, PubMed:37802024). SQSTM1 is itself degraded along with its ubiquitinated cargos (PubMed:16286508, PubMed:17580304, PubMed:37802024). Also required to recruit ubiquitinated proteins to PML bodies in the nucleus (PubMed:20168092). Also involved in autophagy of peroxisomes (pexophagy) in response to reactive oxygen species (ROS) by acting as a bridge between ubiquitinated PEX5 receptor and autophagosomes (PubMed:26344566). Acts as an activator of the NFE2L2/NRF2 pathway via interaction with KEAP1: interaction inactivates the BCR(KEAP1) complex by sequestering the complex in inclusion bodies, promoting nuclear accumulation of NFE2L2/NRF2 and subsequent expression of cytoprotective genes (PubMed:20452972, PubMed:28380357, PubMed:33393215, PubMed:37306101). Promotes relocalization of 'Lys-63'-linked ubiquitinated STING1 to autophagosomes (PubMed:29496741). Involved in endosome organization by retaining vesicles in the perinuclear cloud: following ubiquitination by RNF26, attracts specific vesicle-associated adapters, forming a molecular bridge that restrains cognate vesicles in the perinuclear region and organizes the endosomal pathway for efficient cargo transport (PubMed:27368102, PubMed:33472082). Sequesters tensin TNS2 into cytoplasmic puncta, promoting TNS2 ubiquitination and proteasomal degradation (PubMed:25101860). May regulate the activation of NFKB1 by TNF, nerve growth factor (NGF) and interleukin-1 (PubMed:10356400, PubMed:10747026, PubMed:11244088, PubMed:12471037, PubMed:16079148, PubMed:19931284). May play a role in titin/TTN downstream signaling in muscle cells (PubMed:15802564). Adapter that mediates the interaction between TRAF6 and CYLD (By similarity)

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Frontotemporal dementia and/or amyotrophic lateral sclerosis 3MIM #616437

Myopathy, distal, with rimmed vacuolesMIM #617158

Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onsetMIM #617145

Paget disease of bone 3MIM #167250

Clinical highlights

Gene–disease validity (ClinGen)

Moderate · frontotemporal dementia and/or amyotrophic lateral sclerosis 3 · AD · ClinGen 2022

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

810

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.80

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.80LOEUF

pLI 0.001

Z-score 2.18

OE 0.44 (0.26–0.80)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.94Z-score

OE missense 1.16 (1.06–1.28)

304 obs / 261.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.44 (0.26–0.80)

0≤0.351.4

Missense OE?1.16 (1.06–1.28)

0≤0.61.4

Synonymous OE?1.27

0≤1.21.6

LoF obs/exp: 8 / 18.0Missense obs/exp: 304 / 261.2Syn Z: -2.24

Background carrier burden — how many people carry a rare variant somewhere in SQSTM1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 70

760 rare PASS variants

Rare truncating (LoF)

1 in 1,400

111 rare PASS variants

Rare synonymous (reference)

1 in 120

308 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SQSTM1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 92	1 in 1,600
South Asian	~43k	1 in 48	1 in 470
Remaining (unassigned)	~30k	1 in 69	1 in 1,600
European (Finnish)	~27k	1 in 230	≈ 1 in 6,400
Admixed American	~22k	1 in 47	1 in 3,100
African / African American	~21k	1 in 57	1 in 480
East Asian	~20k	1 in 56	1 in 1,500
Ashkenazi Jewish	~13k	1 in 300	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 57	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 7 of 8 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 8.? see exons ↓