SMARCAL1

Chr 2AR

SNF2 related chromatin remodeling annealing helicase 1

Also known as: HARP, HHARP

NCBI Gene: 50485ENSG00000138375UniProt: Q9NZC9

The protein encoded by this gene is a member of the SWI/SNF family of proteins. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein shows sequence similarity to the E. coli RNA polymerase-binding protein HepA. Mutations in this gene are a cause of Schimke immunoosseous dysplasia (SIOD), an autosomal recessive disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction, and T-cell immunodeficiency. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Schimke immunoosseous dysplasiaMIM #242900
AR
UniProtSchimke immuno-osseous dysplasia
1377
ClinVar variants
67
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— SMARCAL1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
67 Pathogenic / Likely Pathogenic· 238 VUS of 1377 total submissions

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.
0.61LOEUF
pLI 0.000
Z-score 3.55
OE 0.41 (0.28–0.61)
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.
0.84Z-score
OE missense 0.89 (0.83–0.97)
454 obs / 507.6 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.0.41 (0.28–0.61)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.89 (0.83–0.97)
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.1.04
0≤1.21.6
LoF obs/exp: 17 / 41.7Missense obs/exp: 454 / 507.6Syn Z: -0.45

ClinVar Variant Classifications

1377 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic33
Likely Pathogenic34
VUS238
Likely Benign156
Benign2
Conflicting14
33
Pathogenic
34
Likely Pathogenic
238
VUS
156
Likely Benign
2
Benign
14
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
11
1
21
0
33
Likely Pathogenic
21
4
9
0
34
VUS
2
199
28
9
238
Likely Benign
0
4
74
78
156
Benign
0
1
1
0
2
Conflicting
—14
Total3420913387477

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

View in ClinVar →

Protein Context — Lollipop Plot

SMARCAL1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SMARCAL1-related Schimke immunoosseous dysplasia

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersSkinSkeletal
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Schimke immunoosseous dysplasia

MIM #242900

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome.
Warejko JK et al.·Clin J Am Soc Nephrol
2018Cohort
SMARCAL1, the annealing helicase and the transcriptional co-regulator.
Bansal R et al.·IUBMB Life
2020Review
Pan-cancer analysis reveals SMARCAL1 expression is associated with immune cell infiltration and poor prognosis in various cancers.
Zhao WJ et al.·Sci Rep
2025
Cancer-associated SMARCAL1 loss-of-function mutations promote alternative lengthening of telomeres and tumorigenesis in telomerase-negative glioblastoma cells.
Liu H et al.·Neuro Oncol
2023
Ocular manifestations of the genetic causes of focal and segmental glomerulosclerosis.
Zhu V et al.·Pediatr Nephrol
2024Review
SMARCAL1 loss and alternative lengthening of telomeres (ALT) are enriched in giant cell glioblastoma.
Brosnan-Cashman JA et al.·Mod Pathol
2021
Whole genome sequencing identifies monogenic disease in 56.1% of families with early-onset steroid-resistant nephrotic syndrome.
Soliman NA et al.·Hum Genet
2025
Smarcal1 promotes double-strand-break repair by nonhomologous end-joining.
Keka IS et al.·Nucleic Acids Res
2015
ANGPTL3 regulates the peroxisomal translocation of SmarcAL1 in response to cell growth states.
Nagai TH et al.·Sci Rep
2025
Investigation of DNA Damage Response Genes Validates the Role of DNA Repair in Pediatric Cancer Risk and Identifies SMARCAL1 as a Novel Osteosarcoma Predisposition Gene.
Oak N et al.·J Clin Oncol
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools