CBS

Chr 21AR

cystathionine beta-synthase

Also known as: HIP4

NCBI Gene: 875 ENSG00000160200 UniProt: P35520 OMIM: 613381

The encoded protein functions as a homotetramer that catalyzes the conversion of homocysteine to cystathionine in the transsulfuration pathway, using pyridoxal phosphate as a cofactor and activated by adenosyl-methionine. Mutations cause autosomal recessive cystathionine beta-synthase deficiency leading to homocystinuria (both B6-responsive and nonresponsive types) and hyperhomocysteinemic thrombosis. The pathogenic mechanism involves loss of enzymatic function resulting in toxic accumulation of homocysteine.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene acts as a homotetramer to catalyze the conversion of homocysteine to cystathionine, the first step in the transsulfuration pathway. The encoded protein is allosterically activated by adenosyl-methionine and uses pyridoxal phosphate as a cofactor. Defects in this gene can cause cystathionine beta-synthase deficiency (CBSD), which can lead to homocystinuria. This gene is a major contributor to cellular hydrogen sulfide production. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.732 OMIM phenotypes

Clinical Summary— CBS

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Gene-Disease Validity (ClinGen)

classic homocystinuria · ARDefinitive

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

169 unique Pathogenic / Likely Pathogenic· 188 VUS of 874 total submissions

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Clinical Trials

8 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CBS

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?

0.73LOEUF

pLI 0.000

Z-score 2.64

OE 0.45 (0.29–0.73)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.83Z-score

OE missense 0.87 (0.79–0.96)

301 obs / 344.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.45 (0.29–0.73)

0≤0.351.4

Missense OE?0.87 (0.79–0.96)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 12 / 26.7Missense obs/exp: 301 / 344.4Syn Z: -1.11

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCBS-related homocystinuria due to cystathionine beta-synthase deficiencyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.75top 25%

GOF

0.6542th %ile

LOF

0.2582th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

874 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic47

Likely Pathogenic122

VUS188

Likely Benign453

Benign24

Conflicting23

Pathogenic

122

Likely Pathogenic

188

VUS

453

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	34	5	8	0	47
Likely Pathogenic	64	56	2	0	122
VUS	3	155	24	6	188
Likely Benign	0	2	222	229	453
Benign	1	0	23	0	24
Conflicting	—				23
Total	102	218	279	235	857

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

View in ClinVar →

21 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap CBS — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →