ASPM

Chr 1AR

assembly factor for spindle microtubules

Also known as: ASP, Calmbp1, MCPH5

NCBI Gene: 259266 ENSG00000066279 UniProt: Q8IZT6 OMIM: 605481

ASPM encodes a protein essential for normal mitotic spindle function in neuroblasts, with a preferential role in regulating neurogenesis during brain development. Mutations cause primary microcephaly type 5, an autosomal recessive disorder characterized by severely reduced brain size. The pathogenic mechanism involves gain-of-function effects that disrupt normal spindle regulation during neuronal cell division.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene is the human ortholog of the Drosophila melanogaster 'abnormal spindle' gene (asp), which is essential for normal mitotic spindle function in embryonic neuroblasts. Studies in mouse also suggest a role of this gene in mitotic spindle regulation, with a preferential role in regulating neurogenesis. Mutations in this gene are associated with microcephaly primary type 5. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.741 OMIM phenotype

Clinical Summary— ASPM

🧬

Gene-Disease Validity (ClinGen)

autosomal recessive primary microcephaly · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

356 unique Pathogenic / Likely Pathogenic· 1017 VUS of 2226 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — ASPM

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.74LOEUF

pLI 0.000

Z-score 4.39

OE 0.63 (0.54–0.74)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.74Z-score

OE missense 1.05 (1.01–1.09)

1836 obs / 1749.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.63 (0.54–0.74)

0≤0.351.4

Missense OE?1.05 (1.01–1.09)

0≤0.61.4

Synonymous OE?1.17

0≤1.21.6

LoF obs/exp: 105 / 166.1Missense obs/exp: 1836 / 1749.3Syn Z: -3.29

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveASPM-related pirmary microcephalyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6939th %ile

GOF

0.6735th %ile

LOF

0.2485th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

2226 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic261

Likely Pathogenic95

VUS1017

Likely Benign535

Benign73

Conflicting176

261

Pathogenic

Likely Pathogenic

1017

VUS

535

Likely Benign

Benign

176

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	257	0	3	1	261
Likely Pathogenic	90	3	2	0	95
VUS	5	958	26	28	1,017
Likely Benign	1	83	161	290	535
Benign	0	12	46	15	73
Conflicting	—				176
Total	353	1,056	238	334	2,157

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

View in ClinVar →

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