C19ORF12

Chr 19ARAD

chromosome 19 open reading frame 12

Also known as: MPAN, NBIA3, NBIA4, SPG43

NCBI Gene: 83636 ENSG00000131943 UniProt: Q9NSK7 OMIM: 614297

This gene encodes a small transmembrane protein of unknown function. Mutations cause neurodegeneration with brain iron accumulation-4 (NBIA4) and spastic paraplegia 43, inherited in an autosomal recessive pattern. The mechanism of pathogenicity remains unclear given the unknown protein function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

?Spastic paraplegia 43, autosomal recessiveMIM #615043

Neurodegeneration with brain iron accumulation 4MIM #614298

ADAR

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · neurodegeneration with brain iron accumulation 4 · AR · ClinGen 2023

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

1.06

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — C19ORF12

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

0.39Z-score

OE missense 0.89 (0.74–1.06)

84 obs / 94.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.22 (0.08–1.06)

0≤0.351.4

Missense OE?0.89 (0.74–1.06)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 1 / 4.5Missense obs/exp: 84 / 94.7Syn Z: -0.78

Background carrier burden — how many people carry a rare variant somewhere in C19ORF12?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 520

163 rare PASS variants

Rare truncating (LoF)

1 in 2,500

36 rare PASS variants

Rare synonymous (reference)

1 in 540

89 rare PASS variants

Rare missense and truncating variants are carried at similar rates in C19ORF12; this gene does not show strong loss-of-function constraint by this measure. 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 500	1 in 2,900
South Asian	~43k	1 in 230	1 in 1,200
Remaining (unassigned)	~30k	1 in 580	1 in 3,800
European (Finnish)	~27k	1 in 300	≈ 1 in 5,300
Admixed American	~22k	1 in 270	1 in 620
African / African American	~21k	1 in 150	≈ 1 in 4,400
East Asian	~20k	1 in 710	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 650	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 160	≈ 1 in 2,900

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): All 2 coding exons well covered in gnomAD exomes and genomes.? see exons ↓