SRCAP

Chr 16AD

Snf2 related CREBBP activator protein

Also known as: DEHMBA, DOMO1, FLHS, SWR1

NCBI Gene: 10847 ENSG00000080603 UniProt: Q6ZRS2 OMIM: 611421

The protein functions as an ATPase that incorporates the histone variant H2A.Z into nucleosomes and serves as the core catalytic component of the SRCAP chromatin-remodeling complex. Mutations cause Floating-Harbor syndrome, characterized by short stature, language deficits, and dysmorphic facial features, as well as developmental delay with hypotonia, musculoskeletal defects, and behavioral abnormalities. The condition follows autosomal dominant inheritance with loss-of-function being the predicted mechanism of pathogenicity.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

MultiplemechanismADLOEUF 0.102 OMIM phenotypes

Clinical Summary— SRCAP

🧬

Gene-Disease Validity (ClinGen)

Floating-Harbor syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

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

1 unique Pathogenic / Likely Pathogenic· 51 VUS of 100 total submissions

💊

Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.10LOEUF

pLI 1.000

Z-score 9.81

OE 0.05 (0.03–0.10)

Highly constrained

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

Missense Constraint

2.13Z-score

OE missense 0.86 (0.83–0.90)

1634 obs / 1894.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.05 (0.03–0.10)

0≤0.351.4

Missense OE0.86 (0.83–0.90)

0≤0.61.4

Synonymous OE1.15

0≤1.21.6

LoF obs/exp: 6 / 123.8Missense obs/exp: 1634 / 1894.5Syn Z: -3.11

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongSRCAP-related neurodevelopmental disorderLOFAD

definitiveSRCAP-related Floating-Harbor syndromeDNAD

0.3196th %ile

GOF

0.2597th %ile

LOF

0.76top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.10

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNHood et al. (2012) stated that given the structure of SRCAP, the nonrandom clustering of truncating mutations seen in these patients was strongly suggestive of a dominant-negative disease mechanism due to loss of one or more critical domains.PMID:22265015

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