COL22A1

Chr 8

collagen type XXII alpha 1 chain

NCBI Gene: 169044 ENSG00000169436 UniProt: Q8NFW1 OMIM: 610026

The protein is a fibril-associated collagen that stabilizes myotendinous junctions and strengthens skeletal muscle attachments during contractile activity, while also functioning as a cell adhesion ligand for skin epithelial cells and fibroblasts. Mutations cause autosomal recessive myopathy with joint contractures. This gene is not highly constrained against loss-of-function variants, and the associated myopathy primarily affects the musculoskeletal system with characteristic joint involvement.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes member of the collagen family which is thought to contribute to the stabilization of myotendinous junctions and strengthen skeletal muscle attachments during contractile activity. It belongs to the fibril-associated collagens with interrupted triple helix (FACIT) subset of the collagen superfamily, which associate with collagen fibers through their C-terminal collagenous domains and mediate protein-protein interactions through their N-terminal noncollagenous domains. The encoded protein is deposited in the basement membrane zone of the myotendinous junction which is present only at the tissue junctions of muscles, tendons, the heart, articular cartilage, and skin. A knockdown of the orthologous zebrafish gene induces a muscular dystrophy by disruption of the myotendinous junction. [provided by RefSeq, May 2017]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.92

Clinical Summary— COL22A1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

296 VUS of 371 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.92LOEUF

pLI 0.000

Z-score 2.23

OE 0.77 (0.64–0.92)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.37Z-score

OE missense 1.03 (0.98–1.09)

996 obs / 963.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.77 (0.64–0.92)

0≤0.351.4

Missense OE?1.03 (0.98–1.09)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 83 / 108.1Missense obs/exp: 996 / 963.9Syn Z: -1.08

This gene — mechanism propensity

0.6938th %ile

GOF

0.5465th %ile

LOF

0.4627th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

371 submitted variants in ClinVar

ClinVar

Classification Summary

VUS296

Likely Benign17

Benign3

Conflicting2

296

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	293	1	1	296
Likely Benign	0	13	0	4	17
Benign	0	2	0	1	3
Conflicting	—				2
Total	1	308	1	6	318

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

View in ClinVar →

53 pathogenic / likely-pathogenic (of 64) ClinVar copy-number / structural variants overlap COL22A1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →