NUMA1

Chr 11

nuclear mitotic apparatus protein 1

ENSG00000137497 UniProt: Q14980 OMIM: 164009

This gene encodes a microtubule-binding protein that is essential for mitotic spindle formation, chromosome alignment and segregation during cell division, and also serves as a structural component of the nuclear matrix. Mutations cause autosomal dominant neurodevelopmental disorders with intellectual disability, developmental delay, and multiple congenital anomalies. The gene is highly constrained against loss-of-function variants, indicating that even single functional copies may be insufficient for normal development.

OMIM ResearchSummary from RefSeq, UniProt

Microtubule (MT)-binding protein that plays a role in the formation and maintenance of the spindle poles and the alignement and the segregation of chromosomes during mitotic cell division (PubMed:17172455, PubMed:19255246, PubMed:24996901, PubMed:26195665, PubMed:27462074, PubMed:7769006). Functions to tether the minus ends of MTs at the spindle poles, which is critical for the establishment and maintenance of the spindle poles (PubMed:11956313, PubMed:12445386). Plays a role in the establishment of the mitotic spindle orientation during metaphase and elongation during anaphase in a dynein-dynactin-dependent manner (PubMed:23870127, PubMed:24109598, PubMed:24996901, PubMed:26765568). In metaphase, part of a ternary complex composed of GPSM2 and G(i) alpha proteins, that regulates the recruitment and anchorage of the dynein-dynactin complex in the mitotic cell cortex regions situated above the two spindle poles, and hence regulates the correct oritentation of the mitotic spindle (PubMed:22327364, PubMed:23027904, PubMed:23921553). During anaphase, mediates the recruitment and accumulation of the dynein-dynactin complex at the cell membrane of the polar cortical region through direct association with phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), and hence participates in the regulation of the spindle elongation and chromosome segregation (PubMed:22327364, PubMed:23921553, PubMed:24371089, PubMed:24996901). Also binds to other polyanionic phosphoinositides, such as phosphatidylinositol 3-phosphate (PIP), lysophosphatidic acid (LPA) and phosphatidylinositol triphosphate (PIP3), in vitro (PubMed:24371089, PubMed:24996901). Also required for proper orientation of the mitotic spindle during asymmetric cell divisions (PubMed:21816348). Plays a role in mitotic MT aster assembly (PubMed:11163243, PubMed:11229403, PubMed:12445386). Involved in anastral spindle assembly (PubMed:25657325). Positively regulates TNKS protein localization to spindle poles in mitosis (PubMed:16076287). Highly abundant component of the nuclear matrix where it may serve a non-mitotic structural role, occupies the majority of the nuclear volume (PubMed:10075938). Required for epidermal differentiation and hair follicle morphogenesis (By similarity)

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.22

LOEUF· LoF intol.

LOF

Mechanism· predicted

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.22LOEUF

pLI 1.000

Z-score 8.21

OE 0.14 (0.09–0.22)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

0.88Z-score

OE missense 0.93 (0.88–0.98)

1119 obs / 1205.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.14 (0.09–0.22)

0≤0.351.4

Missense OE?0.93 (0.88–0.98)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 15 / 106.4Missense obs/exp: 1119 / 1205.1Syn Z: 0.14

Background carrier burden — how many people carry a rare variant somewhere in NUMA1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 17

2,731 rare PASS variants

Rare truncating (LoF)

1 in 1,300

138 rare PASS variants

Rare synonymous (reference)

1 in 46

1,097 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NUMA1. 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 23	1 in 2,200
South Asian	~43k	1 in 16	1 in 1,500
Remaining (unassigned)	~30k	1 in 16	1 in 1,900
European (Finnish)	~27k	1 in 51	1 in 2,200
Admixed American	~22k	1 in 22	1 in 1,700
African / African American	~21k	1 in 18	1 in 1,100
East Asian	~20k	1 in 22	1 in 820
Ashkenazi Jewish	~13k	1 in 86	none seen
Middle Eastern	~2,884	1 in 19	≈ 1 in 710

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 24 of 25 coding exons well covered in gnomAD exomes; exon 6 marginal. Genomes: 24 of 25 (exon 19 below).? see exons ↓