SQSTM1

Chr 5

sequestosome 1

Also known as: A170, DMRV, EBIAP, FTDALS3, NADGP, OSIL, PDB3, ZIP3

NCBI Gene: 8878 ENSG00000161011 UniProt: Q13501

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.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a multifunctional protein that binds ubiquitin and regulates activation of the nuclear factor kappa-B (NF-kB) signaling pathway. The protein functions as a scaffolding/adaptor protein in concert with TNF receptor-associated factor 6 to mediate activation of NF-kB in response to upstream signals. Alternatively spliced transcript variants encoding either the same or different isoforms have been identified for this gene. Mutations in this gene result in sporadic and familial Paget disease of bone. [provided by RefSeq, Mar 2009]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.80

Clinical Summary— SQSTM1

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Gene-Disease Validity (ClinGen)

frontotemporal dementia and/or amyotrophic lateral sclerosis 3 · ADModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

58 unique Pathogenic / Likely Pathogenic· 471 VUS of 945 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SQSTM1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedSQSTM1-related Paget disease of boneLOFAD

This gene — mechanism propensity

0.6065th %ile

GOF

0.5367th %ile

LOF

0.4233th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 91% of P/LP variants are LoF

GOF1 literature citation

Literature Evidence

GOFRea et al. (2006) demonstrated that transfection of the P392L mutation into HEK293 cells resulted in increased NFKB1 activity compared to wildtype, suggesting a gain of function.1

LOFOur results identify a novel pathogenic SQSTM1 S224X mutation in an atypical FTD patient accompanied with loss of SQSTM1/p62 protein expression probably due to SQSTM1 gene haploinsufficiency.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

945 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic40

Likely Pathogenic18

VUS471

Likely Benign306

Benign48

Conflicting37

Pathogenic

Likely Pathogenic

471

VUS

306

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	36	4	0	0	40
Likely Pathogenic	17	1	0	0	18
VUS	9	411	47	4	471
Likely Benign	1	7	120	178	306
Benign	0	2	38	8	48
Conflicting	—				37
Total	63	425	205	190	920

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

View in ClinVar →

25 pathogenic / likely-pathogenic (of 51) ClinVar copy-number / structural variants overlap SQSTM1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →