C19ORF12

Chr 19ARAD

chromosome 19 open reading frame 12

Also known as: MPAN, NBIA3, NBIA4, SPG43

NCBI Gene: 83636ENSG00000131943UniProt: Q9NSK7

This gene encodes a small transmembrane protein. Mutations in this gene are a cause of neurodegeneration with brain iron accumulation-4 (NBIA4), but the specific function of the encoded protein is unknown. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

Primary Disease Associations & Inheritance

?Spastic paraplegia 43, autosomal recessiveMIM #615043
AR
Neurodegeneration with brain iron accumulation 4MIM #614298
ADAR
363
ClinVar variants
46
Pathogenic / LP
0.34
pLI score
0
Active trials
Clinical Summary— C19ORF12
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.
📋
ClinVar Variants
46 Pathogenic / Likely Pathogenic· 177 VUS of 363 total submissions
Some data sources returned errors (1)

clinvar: 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
Tolerant — LoF & missense variants common in population
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.
1.06LOEUF
pLI 0.344
Z-score 1.52
OE 0.22 (0.08–1.06)
Tolerant

Highly tolerant — LoF variants common in population

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.
0.39Z-score
OE missense 0.89 (0.74–1.06)
84 obs / 94.7 exp
Tolerant

Mild missense constraint

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.0.22 (0.08–1.06)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.89 (0.74–1.06)
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.1.15
0≤1.21.6
LoF obs/exp: 1 / 4.5Missense obs/exp: 84 / 94.7Syn Z: -0.78

ClinVar Variant Classifications

363 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic24
Likely Pathogenic22
VUS177
Likely Benign76
Benign42
Conflicting13
24
Pathogenic
22
Likely Pathogenic
177
VUS
76
Likely Benign
42
Benign
13
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
8
2
14
0
24
Likely Pathogenic
10
7
5
0
22
VUS
10
75
92
0
177
Likely Benign
0
1
35
40
76
Benign
0
1
40
1
42
Conflicting
—13
Total288618641354

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

View in ClinVar →

Protein Context — Lollipop Plot

C19ORF12 · protein map & ClinVar variants

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

Gene2Phenotype Curations

C19orf12-related neurodegeneration with brain iron accumulation

strong
ARLoss Of FunctionAbsent Gene Product
Eye
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Spastic paraplegia 43, autosomal recessive

MIM #615043

Molecular basis of disorder known

Autosomal recessive

Neurodegeneration with brain iron accumulation 4

MIM #614298

Molecular basis of disorder known

Autosomal dominantAutosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Neurodegeneration with brain iron accumulation.
Hayflick SJ et al.·Handb Clin Neurol
2018Review
Pantothenate kinase-associated neurodegeneration.
Hartig MB et al.·Curr Drug Targets
2012Review
C19orf12 ablation causes ferroptosis in mitochondrial membrane protein-associated with neurodegeneration.
Shao C et al.·Free Radic Biol Med
2022
SPG43 and ALS-like syndrome in the same family due to compound heterozygous mutations of the C19orf12 gene: a case description and brief review.
Remiche G et al.·Neurogenetics
2021Review
C19orf12 gene variants causing mitochondrial membrane protein-associated neurodegeneration (MPAN).
Kumari R et al.·Eur J Hum Genet
2025
Metabolic alterations in fibroblasts of patients presenting with the MPAN subtype of neurodegeneration with brain iron accumulation (NBIA).
Wydrych A et al.·Biochim Biophys Acta Mol Basis Dis
2025Cohort
Mitochondrial membrane protein-associated neurodegeneration (MPAN).
Hartig M et al.·Int Rev Neurobiol
2013Review
Neurodegeneration with brain iron accumulation: Insights into the mitochondria dysregulation.
Wang ZB et al.·Biomed Pharmacother
2019Review
A novel C19orf12 frameshift mutation in a MPAN pedigree impairs mitochondrial function and connectivity leading to neurodegeneration.
Chen HY et al.·Parkinsonism Relat Disord
2023
A Clinical and Integrated Genetic Study of Isolated and Combined Dystonia in Taiwan.
Wu MC et al.·J Mol Diagn
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Autophagy-related proteomics reveals lysosomal alterations linked to C19orf12 mutations and candidate biomarkers in MPAN patients' fibroblasts.
Pakula B et al.·Neurobiol Dis
2026Cohort
Inflammation and oligoclonal bands in cerebrospinal fluid in neurodegeneration associated with C19orf12 mutations.
Skowrońska M et al.·Parkinsonism Relat Disord
2026
Distinct Neurodegenerative Pathways in Two NBIA Subtypes: Inflammatory Activation in C19orf12 but Not in PANK2 Mutation Carriers.
Skowrońska M et al.·Cells
2025🔓 Open Access
Loss of mouse C19orf12 homolog disturbs tubular ER homeostasis and leads to neuroaxonal dystrophy.
Wu F et al.·Acta Neuropathol Commun
2025🔓 Open AccessFunctional
C19orf12 inhibits mitochondrial function and enhances the antitumor effects of metformin in non-small cell lung cancer.
Liu R et al.·Cell Rep
2025
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