SMARCA5

Chr 4

SNF2 related chromatin remodeling ATPase 5

Also known as: ISWI, SNF2H, WCRF135, hISWI, hSNF2H

NCBI Gene: 8467 ENSG00000153147 UniProt: O60264

SMARCA5 encodes an ATPase that catalyzes chromatin remodeling by sliding nucleosomes along DNA to facilitate transcription, DNA replication, and repair processes. Mutations cause autosomal dominant neurodevelopmental disorders with intellectual disability, developmental delay, and various neurological features. The gene is extremely intolerant to loss-of-function variants (pLI ~1.0, LOEUF 0.074), indicating that even mild reductions in protein function can cause disease.

ResearchSummary from RefSeq, UniProt

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 protein encoded by this gene is a component of the chromatin remodeling and spacing factor RSF, a facilitator of the transcription of class II genes by RNA polymerase II. The encoded protein is similar in sequence to the Drosophila ISWI chromatin remodeling protein. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.07

Clinical Summary— SMARCA5

🧬

Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADModerate

Moderate evidence — consider for supplementary testing

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

9 unique Pathogenic / Likely Pathogenic· 110 VUS of 156 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.07LOEUF

pLI 1.000

Z-score 7.28

OE 0.02 (0.01–0.07)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

5.42Z-score

OE missense 0.35 (0.32–0.40)

198 obs / 558.2 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.02 (0.01–0.07)

0≤0.351.4

Missense OE?0.35 (0.32–0.40)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 1 / 63.7Missense obs/exp: 198 / 558.2Syn Z: 1.18

This gene — mechanism propensity

0.3097th %ile

GOF

0.2696th %ile

LOF

0.79top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 22% of P/LP variants are LoF · LOEUF 0.07

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

ClinVar Variant Classifications

156 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic6

VUS110

Likely Benign8

Benign1

Conflicting2

Pathogenic

Likely Pathogenic

110

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	2	0	0	3
Likely Pathogenic	1	5	0	0	6
VUS	4	104	2	0	110
Likely Benign	0	1	2	5	8
Benign	0	0	1	0	1
Conflicting	—				2
Total	6	112	5	5	130

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

View in ClinVar →

29 pathogenic / likely-pathogenic (of 32) ClinVar copy-number / structural variants overlap SMARCA5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →