ARK2C

Chr 18

arkadia (RNF111) C-terminal like ring finger ubiquitin ligase 2C

Also known as: ARKL2, RNF111L2, RNF165, lncAMPC

NCBI Gene: 494470 ENSG00000141622 UniProt: Q6ZSG1

This gene encodes an E3 ubiquitin-protein ligase that regulates motor axon elongation by enhancing BMP signaling through ubiquitination and degradation of SMAD inhibitors. Mutations cause autosomal recessive spinal muscular atrophy with congenital bone fractures, affecting both the neuromuscular system and skeletal development. The gene is highly constrained against loss-of-function variants (pLI 0.97, LOEUF 0.32), indicating intolerance to protein-truncating mutations.

ResearchSummary from RefSeq, UniProt

Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in motor neuron axon guidance and positive regulation of BMP signaling pathway. Predicted to act upstream of or within several processes, including forelimb morphogenesis; nervous system development; and protein polyubiquitination. Predicted to be part of protein-containing complex. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.32

LOEUF· LoF intol.

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.32LOEUF

pLI 0.972

Z-score 3.71

OE 0.10 (0.04–0.32)

Highly constrained

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

Missense Constraint?

1.94Z-score

OE missense 0.63 (0.54–0.72)

134 obs / 213.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.10 (0.04–0.32)

0≤0.351.4

Missense OE?0.63 (0.54–0.72)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 2 / 19.8Missense obs/exp: 134 / 213.8Syn Z: -0.13

Background carrier burden — how many people carry a rare variant somewhere in ARK2C?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 240

423 rare PASS variants

Rare truncating (LoF)

1 in 3,400

49 rare PASS variants

Rare synonymous (reference)

1 in 270

233 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ARK2C. 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 310	1 in 3,200
South Asian	~43k	1 in 220	≈ 1 in 18,000
Remaining (unassigned)	~30k	1 in 170	1 in 2,800
European (Finnish)	~27k	1 in 770	1 in 2,100
Admixed American	~22k	1 in 250	1 in 2,400
African / African American	~21k	1 in 160	1 in 2,500
East Asian	~20k	1 in 200	≈ 1 in 5,700
Ashkenazi Jewish	~13k	1 in 1,600	none seen
Middle Eastern	~2,884	1 in 300	≈ 1 in 660

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): 7 of 8 coding exons well covered in gnomAD exomes; exon 7 marginal. Genomes: all 8.? see exons ↓