NUP214

Chr 9AR

nucleoporin 214

Also known as: CAIN, CAN, IIAE9

NCBI Gene: 8021 ENSG00000126883 UniProt: P35658 OMIM: 114350

The protein is a nucleoporin that forms part of the nuclear pore complex and is essential for nucleocytoplasmic transport and proper cell cycle progression. Mutations cause autosomal recessive acute infection-induced encephalopathy with increased susceptibility during febrile episodes. The gene is highly constrained against loss-of-function variation (LOEUF 0.35), indicating that biallelic mutations likely have severe consequences for cellular function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The nuclear pore complex is a massive structure that extends across the nuclear envelope, forming a gateway that regulates the flow of macromolecules between the nucleus and the cytoplasm. Nucleoporins are the main components of the nuclear pore complex in eukaryotic cells. This gene is a member of the FG-repeat-containing nucleoporins. The protein encoded by this gene is localized to the cytoplasmic face of the nuclear pore complex where it is required for proper cell cycle progression and nucleocytoplasmic transport. The 3' portion of this gene forms a fusion gene with the DEK gene on chromosome 6 in a t(6,9) translocation associated with acute myeloid leukemia and myelodysplastic syndrome. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

{Encephalopathy, acute, infection-induced, susceptibility to, 9}MIM #618426

Leukemia, acute myeloid, somaticMIM #601626

Leukemia, T-cell acute lymphoblastic, somaticMIM #613065

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Leukemia, acute myeloid, somatic; Leukemia, T-cell acute lymphoblastic, somatic; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.35

LOEUF· LoF intol.

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.35LOEUF

pLI 0.055

Z-score 6.53

OE 0.24 (0.17–0.35)

Highly constrained

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

Missense Constraint?

0.65Z-score

OE missense 0.95 (0.90–0.99)

1063 obs / 1124.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.24 (0.17–0.35)

0≤0.351.4

Missense OE?0.95 (0.90–0.99)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 21 / 86.5Missense obs/exp: 1063 / 1124.7Syn Z: -0.31

Background carrier burden — how many people carry a rare variant somewhere in NUP214?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 20

2,762 rare PASS variants

Rare truncating (LoF)

1 in 430

271 rare PASS variants

Rare synonymous (reference)

1 in 45

1,053 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NUP214. 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 26	1 in 520
South Asian	~43k	1 in 20	1 in 230
Remaining (unassigned)	~30k	1 in 18	1 in 320
European (Finnish)	~27k	1 in 61	1 in 350
Admixed American	~22k	1 in 22	1 in 420
African / African American	~21k	1 in 22	1 in 490
East Asian	~20k	1 in 26	1 in 460
Ashkenazi Jewish	~13k	1 in 98	1 in 710
Middle Eastern	~2,884	1 in 24	≈ 1 in 1,400

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): 33 of 36 coding exons well covered in gnomAD exomes; exons 8, 25, 27 marginal. Genomes: 34 of 36 (exons 10, 27 below).? see exons ↓