EXT2

Chr 11ADAR

exostosin glycosyltransferase 2

Also known as: SOTV, SSMS

NCBI Gene: 2132 ENSG00000151348 UniProt: Q93063 OMIM: 133701

This gene encodes a glycosyltransferase that catalyzes chain elongation during heparan sulfate biosynthesis in the Golgi apparatus. Mutations cause multiple exostoses type 2 and seizures, scoliosis, and macrocephaly syndrome through both autosomal dominant and autosomal recessive inheritance patterns. The pathogenic mechanism involves dominant negative effects that disrupt normal heparan sulfate production.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes one of two glycosyltransferases involved in the chain elongation step of heparan sulfate biosynthesis. Mutations in this gene cause the type II form of multiple exostoses. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.773 OMIM phenotypes

Clinical Summary— EXT2

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Gene-Disease Validity (ClinGen)

exostoses, multiple, type 2 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

243 unique Pathogenic / Likely Pathogenic· 407 VUS of 1041 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — EXT2

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?

0.77LOEUF

pLI 0.000

Z-score 2.73

OE 0.53 (0.38–0.77)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.64Z-score

OE missense 0.91 (0.84–0.99)

394 obs / 431.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.53 (0.38–0.77)

0≤0.351.4

Missense OE?0.91 (0.84–0.99)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 21 / 39.5Missense obs/exp: 394 / 431.4Syn Z: -0.24

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveEXT2-related multiple exostosesLOFAD

This gene — mechanism propensity

0.6259th %ile

GOF

0.5366th %ile

LOF

0.3261th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 86% of P/LP variants are LoF · ClinGen HI: Sufficient evidence for dosage pathogenicity

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.

Literature Evidence

LOFAnalysis of mutations in EXT1 and EXT2 in Brazilian patients with multiple osteochondromas1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 29529714 ↗

ClinVar Variant Classifications

1041 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic199

Likely Pathogenic44

VUS407

Likely Benign263

Benign57

Conflicting49

199

Pathogenic

Likely Pathogenic

407

VUS

263

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	175	6	18	0	199
Likely Pathogenic	33	9	0	2	44
VUS	6	364	30	7	407
Likely Benign	0	20	93	150	263
Benign	0	6	44	7	57
Conflicting	—				49
Total	214	405	185	166	1,019

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap EXT2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →