CCDC22

Chr XXLR

CCC complex scaffolding subunit CCDC22

Also known as: CXorf37, JM1, RTSC2

NCBI Gene: 28952ENSG00000101997UniProt: O60826

This gene encodes a protein containing a coiled-coil domain. The encoded protein functions in the regulation of NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) by interacting with COMMD (copper metabolism Murr1 domain-containing) proteins. The mouse orthologous protein has been shown to bind copines, which are calcium-dependent, membrane-binding proteins that may function in calcium signaling. This human gene has been identified as a novel candidate gene for syndromic X-linked intellectual disability. [provided by RefSeq, Aug 2013]

Primary Disease Associations & Inheritance

Ritscher-Schinzel syndrome 2MIM #300963
XLR
279
ClinVar variants
72
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— CCDC22
🧬
Gene-Disease Validity (ClinGen)
Ritscher-Schinzel syndrome 2 · XLModerate

Moderate evidence — consider for supplementary testing

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
72 Pathogenic / Likely Pathogenic· 150 VUS of 279 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.12LOEUF
pLI 1.000
Z-score 4.56
OE 0.00 (0.00–0.12)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

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.
1.29Z-score
OE missense 0.78 (0.70–0.87)
211 obs / 270.7 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.0.00 (0.00–0.12)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.78 (0.70–0.87)
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.1.01
0≤1.21.6
LoF obs/exp: 0 / 24.2Missense obs/exp: 211 / 270.7Syn Z: -0.09

ClinVar Variant Classifications

279 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic70
Likely Pathogenic2
VUS150
Likely Benign36
Benign6
Conflicting15
70
Pathogenic
2
Likely Pathogenic
150
VUS
36
Likely Benign
6
Benign
15
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
70
0
70
Likely Pathogenic
0
1
1
0
2
VUS
3
130
16
1
150
Likely Benign
0
10
4
22
36
Benign
0
2
2
2
6
Conflicting
—15
Total31439325279

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

View in ClinVar →

Protein Context — Lollipop Plot

CCDC22 · protein map & ClinVar variants

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

Gene2Phenotype Curations

CCDC22-related syndromic intellectual disability

strong
Monoallelic X HemizygousUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Ritscher-Schinzel syndrome 2

MIM #300963

Molecular basis of disorder known

X-linked recessive
📖
GeneReview available — CCDC22
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Expanding the pre- and postnatal phenotype of WASHC5 and CCDC22 -related Ritscher-Schinzel syndromes.
Neri S et al.·Eur J Med Genet
2022
Expansion of the CCDC22 associated Ritscher-Schinzel/3C syndrome and review of the literature: Should the minimal diagnostic criteria be revised?
Gjerulfsen CE et al.·Eur J Med Genet
2021Review
CCDC22 mutations that impair COMMD binding cause attenuated 3C/Ritscher-Schinzel syndrome.
Singla A et al.·BMC Med Genomics
2025
CCDC22 variants caused X-linked focal epilepsy and focal cortical dysplasia.
He YL et al.·Seizure
2024Case report
Clinical diversity and molecular mechanism of VPS35L-associated Ritscher-Schinzel syndrome.
Otsuji S et al.·J Med Genet
2023Functional
Evaluating the clinical utility and strategy of whole-exome sequencing testing for fetuses with increased nuchal translucency.
Zhou F et al.·Am J Obstet Gynecol
2025
Delineating the CCDC22-related Ritscher-Schinzel syndrome phenotype in the original family.
Rodgers J et al.·Am J Med Genet A
2022Case report
Missense variant in CCDC22 causes X-linked recessive intellectual disability with features of Ritscher-Schinzel/3C syndrome.
Kolanczyk M et al.·Eur J Hum Genet
2015Case report
Association between rs2294020 in X-linked CCDC22 and susceptibility to autoimmune diseases with focus on systemic lupus erythematosus.
D'Amico F et al.·Immunol Lett
2017
[Ritscher-Schinzel syndrome caused by CCDC22 gene mutation: a case report].
Liang YT et al.·Zhongguo Dang Dai Er Ke Za Zhi
2020Case report
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