CHSY1

Chr 15

chondroitin sulfate synthase 1

Also known as: CHSY, CSS1, ChSy-1, TPBS

NCBI Gene: 22856 ENSG00000131873 UniProt: Q86X52

This protein functions as a dual transferase enzyme that synthesizes chondroitin sulfate by adding both glucuronic acid and N-acetylgalactosamine to the growing polymer chain, and negatively regulates bone formation through modulation of NOTCH signaling. Mutations cause Temtamy preaxial brachydactyly syndrome, which involves limb malformations, inherited in an autosomal recessive pattern. The gene shows high constraint against loss-of-function variants (LOEUF 0.405), indicating that such mutations are typically not tolerated.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the chondroitin N-acetylgalactosaminyltransferase family. These enzymes possess dual glucuronyltransferase and galactosaminyltransferase activity and play critical roles in the biosynthesis of chondroitin sulfate, a glycosaminoglycan involved in many biological processes including cell proliferation and morphogenesis. Decreased expression of this gene may play a role in colorectal cancer, and mutations in this gene are a cause of temtamy preaxial brachydactyly syndrome. [provided by RefSeq, Dec 2011]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtTemtamy preaxial brachydactyly syndrome

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · temtamy preaxial brachydactyly syndrome · AR · ClinGen 2026

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

0.41

LOEUF

LOF

Mechanism· G2P

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.41LOEUF

pLI 0.708

Z-score 3.81

OE 0.19 (0.10–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.83Z-score

OE missense 0.89 (0.81–0.96)

376 obs / 424.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.19 (0.10–0.41)

0≤0.351.4

Missense OE?0.89 (0.81–0.96)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 5 / 26.0Missense obs/exp: 376 / 424.1Syn Z: -1.96

Background carrier burden — how many people carry a rare variant somewhere in CHSY1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 69

1,023 rare PASS variants

Rare truncating (LoF)

1 in 6,100

58 rare PASS variants

Rare synonymous (reference)

1 in 64

496 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CHSY1. 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 76	1 in 6,100
South Asian	~43k	1 in 46	1 in 6,000
Remaining (unassigned)	~30k	1 in 56	≈ 1 in 8,100
European (Finnish)	~27k	1 in 200	1 in 2,400
Admixed American	~22k	1 in 72	≈ 1 in 22,000
African / African American	~21k	1 in 46	≈ 1 in 6,400
East Asian	~20k	1 in 74	≈ 1 in 14,000
Ashkenazi Jewish	~13k	1 in 250	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 77	none seen

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): 2 of 3 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 3.? see exons ↓