SPIRE2

Chr 16

spire type actin nucleation factor 2

Also known as: Spir-2

NCBI Gene: 84501 ENSG00000204991 UniProt: Q8WWL2 OMIM: 609217

SPIRE2 encodes an actin nucleation factor that assembles actin filaments and is involved in intracellular vesicle transport, spindle positioning during cell division, and nuclear actin filament formation in response to DNA damage. Mutations in SPIRE2 cause autosomal recessive primary microcephaly with seizures and developmental delay. This gene is not highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable microtubule binding activity. Involved in establishment of meiotic spindle localization; formin-nucleated actin cable assembly; and positive regulation of double-strand break repair. Predicted to be located in cleavage furrow. Predicted to be active in cell cortex and cytoplasmic vesicle membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.86

Clinical Summary— SPIRE2

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.86LOEUF

pLI 0.000

Z-score 2.18

OE 0.59 (0.41–0.86)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.26Z-score

OE missense 1.04 (0.96–1.12)

448 obs / 432.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.59 (0.41–0.86)

0≤0.351.4

Missense OE?1.04 (0.96–1.12)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 19 / 32.4Missense obs/exp: 448 / 432.8Syn Z: -1.58

This gene — mechanism propensity

0.6842th %ile

GOF

0.7028th %ile

LOF

0.3941th %ile

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

GOFprediction above median

DNprediction above median

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.