CBS

Chr 21AR

cystathionine beta-synthase

Also known as: HIP4

NCBI Gene: 875ENSG00000160200UniProt: P35520

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]

Primary Disease Associations & Inheritance

Homocystinuria, B6-responsive and nonresponsive typesMIM #236200
AR
Thrombosis, hyperhomocysteinemicMIM #236200
AR
UniProtCystathionine beta-synthase deficiency
483
ClinVar variants
118
Pathogenic / LP
0.00
pLI score
7
Active trials
Clinical Summary— CBS
🧬
Gene-Disease Validity (ClinGen)
classic homocystinuria · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
118 Pathogenic / Likely Pathogenic· 75 VUS of 483 total submissions
💊
Clinical Trials
7 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.73LOEUF
pLI 0.000
Z-score 2.64
OE 0.45 (0.29–0.73)
Tolerant

Typical tolerance to LoF variation

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.
0.83Z-score
OE missense 0.87 (0.79–0.96)
301 obs / 344.4 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.0.45 (0.29–0.73)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.87 (0.79–0.96)
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.1.11
0≤1.21.6
LoF obs/exp: 12 / 26.7Missense obs/exp: 301 / 344.4Syn Z: -1.11

ClinVar Variant Classifications

483 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic71
Likely Pathogenic47
VUS75
Likely Benign242
Benign24
Conflicting24
71
Pathogenic
47
Likely Pathogenic
75
VUS
242
Likely Benign
24
Benign
24
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
10
6
55
0
71
Likely Pathogenic
17
26
4
0
47
VUS
0
62
9
4
75
Likely Benign
0
1
116
125
242
Benign
0
0
21
3
24
Conflicting
—24
Total2795205132483

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

View in ClinVar →

Protein Context — Lollipop Plot

CBS · protein map & ClinVar variants

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

Gene2Phenotype Curations

CBS-related homocystinuria due to cystathionine beta-synthase deficiency

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEyeSkin
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Homocystinuria, B6-responsive and nonresponsive types

MIM #236200

Molecular basis of disorder known

Autosomal recessive

Thrombosis, hyperhomocysteinemic

MIM #236200

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — CBS
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Frontotemporal Dementia.
Olney NT et al.·Neurol Clin
2017Review
Criteria for the diagnosis of corticobasal degeneration.
Armstrong MJ et al.·Neurology
2013
Progressive Supranuclear Palsy and Corticobasal Syndrome.
Pantelyat A·Continuum (Minneap Minn)
2022Review
Corticobasal degeneration: An update.
Révész T et al.·Ideggyogy Sz
2024Review
Corticobasal degeneration.
Saranza GM et al.·Int Rev Neurobiol
2019Review
Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome.
Jabbari E et al.·JAMA Neurol
2020
PET-based classification of corticobasal syndrome.
Nakano Y et al.·Parkinsonism Relat Disord
2022
A Biomarker-Based Classification of Corticobasal Syndrome.
Palleis C et al.·Mov Disord
2026
Progressive Supranuclear Palsy and Corticobasal Syndrome.
McFarland NR·Continuum (Minneap Minn)
2025Review
Treatment of inherited homocystinurias.
Schiff M et al.·Neuropediatrics
2012Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Fluorescence-based determination of cyclic adenosine monophosphate in nasal secretions of healthy and post COVID-19 patients using Tinopal CBS-X.
Imam MS et al.·Anal Methods
2026Cohort
Unveiling clinical and genetic landscapes of MMA and CBS: insights from whole exome sequencing in a tertiary care setting.
Wasim M et al.·Pediatr Res
2026
The H2S donor sulforaphane inhibits NLRP3 inflammasome activation by inducing mitochondrial autophagy and mitigating CBS-H2S axis damage in in-vitro and in-vivo models of Parkinson's disease.
Xie W et al.·Bioorg Chem
2026Functional
Safety and efficacy of a feed additive consisting of alpha-galactosidase (produced with Aspergillus tubingensisATCC SD 6740) and endo-1,4-beta-xylanase (produced with Trichoderma orientaleCBS 139997) (Capsozyme SB Plus) for weaned piglets (Industrial Técnica Pecuaria, S.A.).
EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) et al.·EFSA J
2026🔓 Open Access
Safety evaluation of the food enzyme containing endo-1,4-β-xylanase and endo-1,3(4)-β-glucanase from the non-genetically modified Aspergillus tubingensis strain CBS 138353.
EFSA Panel on Food Enzymes (FEZ) et al.·EFSA J
2026🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
PSPPSP - Progressive Supranuclear PalsyCorticobasal Syndrome

The CurePSP Genetics Program

RECRUITING
NCT06647641Massachusetts General HospitalStarted 2024-10-08
Whole genome sequencing will be performed at the NIH
ALSFTD

Effects of Probiotics in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia Spectrum Disorder (ALS-FTDSD) Patients

RECRUITING
NCT06051123Phase NACentre hospitalier de l'Université de Montréal (CHUM)Started 2024-01-01
ProbioticPlacebo
ALS

Amyotrophic Lateral Sclerosis (ALS) Families Project

RECRUITING
NCT03865420Columbia UniversityStarted 2018-09-11
Amyotrophic Lateral Sclerosis

Personalized Antisense Oligonucleotide Therapy for A Single Patient With CHCHD10 ALS (nL18576)

NOT YET RECRUITING
NCT07423494Phase PHASE1, PHASE2n-Lorem FoundationStarted 2026-03
nL-CHCHD-001
Obesity and OverweightPre-diabeticType 2 Diabetes Mellitus (T2DM)

Targeted Precision Nutrition Strategy To Prevent Chronic Metabolic Diseases

RECRUITING
NCT06923644Phase NAMaastricht University Medical CenterStarted 2025-04-23
Optimal Metabotype-specific dietSub-optimal diet
Progressive Supranuclear PalsyMultiple System AtrophyCorticobasal Syndrome

The NADAPT Study: a Randomized Double-blind Trial of NAD Replenishment Therapy for Atypical Parkinsonism

RECRUITING
NCT06162013Phase PHASE2Haukeland University HospitalStarted 2024-03-05
Nicotinamide RibosidePlacebo
SepsisARDSCritical Illness

Early Severe Illness TrAnslational BioLogy InformaticS in Humans

RECRUITING
NCT05591924London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph'sStarted 2024-04-26
PhelebotomyBroncheoalveolar LavageTracheal Aspirate

External Resources

Links to major genomics databases and tools