UNC80

Chr 2AR

unc-80 homolog, NALCN channel complex subunit

NCBI Gene: 285175ENSG00000144406UniProt: Q8N2C7

Auxiliary subunit of the NALCN sodium channel complex, a voltage-gated ion channel responsible for the resting Na(+) permeability that controls neuronal excitability (By similarity). Activated by neuropeptides substance P, neurotensin, and extracellular Ca(2+) that regulates neuronal excitability by controlling the sizes of NALCN-dependent sodium-leak current. UNC80 is essential for NALCN sensitivity to extracellular Ca(2+) (By similarity)

Primary Disease Associations & Inheritance

Hypotonia, infantile, with psychomotor retardation and characteristic facies 2MIM #616801
AR
591
ClinVar variants
43
Pathogenic / LP
0.05
pLI score
0
Active trials
Clinical Summary— UNC80
🧬
Gene-Disease Validity (ClinGen)
hypotonia, infantile, with psychomotor retardation and characteristic facies 2 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.
📋
ClinVar Variants
43 Pathogenic / Likely Pathogenic· 231 VUS of 591 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.24 (0.18–0.31)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.63 (0.59–0.66)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.81
0≤1.21.6
LoF obs/exp: 39 / 165.8Missense obs/exp: 1089 / 1738.0Syn Z: 3.79

ClinVar Variant Classifications

591 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic23
Likely Pathogenic20
VUS231
Likely Benign312
Benign3
Conflicting2
23
Pathogenic
20
Likely Pathogenic
231
VUS
312
Likely Benign
3
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
10
0
13
0
23
Likely Pathogenic
17
0
3
0
20
VUS
1
219
8
3
231
Likely Benign
0
2
116
194
312
Benign
0
0
2
1
3
Conflicting
—2
Total28221142198591

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

View in ClinVar →

Protein Context — Lollipop Plot

UNC80 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

UNC80-related persistent hypotonia, encephalopathy, growth retardation, and severe intellectual disability

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Hypotonia, infantile, with psychomotor retardation and characteristic facies 2

MIM #616801

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — UNC80
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genotype-Phenotype Landscape of NALCN and UNC80-Related Disorders.
Parra-Díaz P et al.·Neurology
2025
A new neurodevelopmental disorder linked to heterozygous variants in UNC79.
Bayat A et al.·Genet Med
2023
Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex.
Wie J et al.·Nat Commun
2020
Phenotypic evolution of UNC80 loss of function.
Valkanas E et al.·Am J Med Genet A
2016
Identification of a novel homozygous UNC80 variant in a child with infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2).
Obeid T et al.·Metab Brain Dis
2018Case report
Novel nonsense mutation in UNC80 in a Turkish patient further validates the sociable skill and severe gastrointestinal problems as part of disease spectrum.
Kelesoglu FM et al.·Am J Med Genet A
2023Case report
Genetic variants in components of the NALCN-UNC80-UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies).
Bramswig NC et al.·Hum Genet
2018Case report
Mutations in UNC80, Encoding Part of the UNC79-UNC80-NALCN Channel Complex, Cause Autosomal-Recessive Severe Infantile Encephalopathy.
Shamseldin HE et al.·Am J Hum Genet
2016Case report
Case Report of Pediatric Channelopathies With UNC80 and KCNJ11 Mutations Having Abnormal Respiratory Control Treated With Positive Airway Pressure Therapy.
Hong H et al.·J Clin Sleep Med
2018Case report
UNC80 mutation causes a syndrome of hypotonia, severe intellectual disability, dyskinesia and dysmorphism, similar to that caused by mutations in its interacting cation channel NALCN.
Perez Y et al.·J Med Genet
2016
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools