ASPM

Chr 1AR

assembly factor for spindle microtubules

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

Involved in mitotic spindle regulation and coordination of mitotic processes. The function in regulating microtubule dynamics at spindle poles including spindle orientation, astral microtubule density and poleward microtubule flux seems to depend on the association with the katanin complex formed by KATNA1 and KATNB1. Enhances the microtubule lattice severing activity of KATNA1 by recruiting the katanin complex to microtubules. Can block microtubule minus-end growth and reversely this function can be enhanced by the katanin complex (PubMed:28436967). May have a preferential role in regulating neurogenesis

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Microcephaly 5, primary, autosomal recessiveMIM #608716

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · autosomal recessive primary microcephaly · AR · ClinGen 2024
Definitive · microcephaly 5, primary, autosomal recessive · AR · G2P

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.74

LOEUF

LOF

Mechanism· G2P

📖

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

Background carrier burden — how many people carry a rare variant somewhere in ASPM?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 11

4,484 rare PASS variants

Rare truncating (LoF)

1 in 120

708 rare PASS variants

Rare synonymous (reference)

1 in 33

1,529 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ASPM. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 18	1 in 140
South Asian	~43k	1 in 12	1 in 230
Remaining (unassigned)	~30k	1 in 10	1 in 210
European (Finnish)	~27k	1 in 41	1 in 250
Admixed American	~22k	1 in 13	1 in 150
African / African American	~21k	1 in 11	1 in 150
East Asian	~20k	1 in 15	1 in 200
Ashkenazi Jewish	~13k	1 in 78	1 in 640
Middle Eastern	~2,884	1 in 14	1 in 480

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.