UNC80

Chr 2

unc-80 subunit of NALCN channel complex

Also known as: C2orf21, UNC-80

NCBI Gene: 285175 ENSG00000144406 UniProt: Q8N2C7

The protein serves as a bridge component and Src kinase scaffold in voltage-independent sodium leak channel complexes that establish and maintain neuronal resting membrane potentials. Biallelic mutations cause hypotonia, infantile, with psychomotor retardation and characteristic facies 2, an autosomal recessive disorder presenting with congenital infantile encephalopathy, intellectual disability, and growth issues. The pathogenic mechanism involves disruption of neuronal membrane potential regulation through impaired leak channel function.

ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a component of a voltage-independent 'leak' ion-channel complex, in which it performs essential functions, such as serving as a bridge between two other components (sodium leak channel non-selective and UNC79) and as a scaffold for Src kinases. Leak channels play an importnat role in establishment and maintenance of resting membrane potentials in neurons. Mutations in this gene are associated with congenital infantile encephalopathy, intellectual disability and growth issues. [provided by RefSeq, Aug 2016]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtHypotonia, infantile, with psychomotor retardation and characteristic facies 2

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · hypotonia, infantile, with psychomotor retardation and characteristic facies 2 · AR · ClinGen 2021

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

0.31

LOEUF· LoF intol.

LOF

Mechanism· G2P

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.31LOEUF

pLI 0.052

Z-score 9.12

OE 0.24 (0.18–0.31)

Highly constrained

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

Missense Constraint?

5.53Z-score

OE missense 0.63 (0.59–0.66)

1089 obs / 1738.0 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.24 (0.18–0.31)

0≤0.351.4

Missense OE?0.63 (0.59–0.66)

0≤0.61.4

Synonymous OE?0.81

0≤1.21.6

LoF obs/exp: 39 / 165.8Missense obs/exp: 1089 / 1738.0Syn Z: 3.79

Background carrier burden — how many people carry a rare variant somewhere in UNC80?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 21

3,589 rare PASS variants

Rare truncating (LoF)

1 in 660

326 rare PASS variants

Rare synonymous (reference)

1 in 30

1,579 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for UNC80. 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 730
South Asian	~43k	1 in 18	1 in 610
Remaining (unassigned)	~30k	1 in 21	1 in 540
European (Finnish)	~27k	1 in 50	1 in 1,200
Admixed American	~22k	1 in 19	1 in 650
African / African American	~21k	1 in 22	1 in 540
East Asian	~20k	1 in 21	1 in 300
Ashkenazi Jewish	~13k	1 in 62	1 in 780
Middle Eastern	~2,884	1 in 22	1 in 560

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.