# NM_000071.3(CBS):c.1080C>T (p.Ala360=)

https://sugi.bio/variant/cbs-p-ala360

## Summary

**CBS p.Ala360= (c.1080C>T)** is classified **Benign** in CBS (ClinVar, Multiple submitters, 19 submitters; last evaluated 2026-02-04). Common (popmax 60.9%, eas) — too common for a highly-penetrant pathogenic allele; Associated with classic homocystinuria.

**At a glance:** Benign · review: Multiple submitters · rsID rs1801181 · 19 submitters · 2 linked conditions · common (popmax 60.9%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the CBS gene that is classified as benign — not considered disease-causing, submitted by 19 submitters, and is linked to classic homocystinuria.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-9 / 1 000 000 (Worldwide) |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CBS is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Homocystinuria due to cystathionine beta-synthase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Dental crowding — Very frequent (99-80%)
- Osteoporosis — Very frequent (99-80%)
- Ectopia lentis — Very frequent (99-80%)
- Arachnodactyly — Very frequent (99-80%)
- Intellectual disability — Very frequent (99-80%)
- Disproportionate tall stature — Very frequent (99-80%)
- Hyperhomocystinemia — Very frequent (99-80%)
- Recurrent fractures — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006667/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CBS](https://sugi.bio/atlas/gene/CBS/) |
| Protein change (HGVS p.) | p.Ala360= |
| Coding change (HGVS c.) | c.1080C>T |
| MANE Select transcript | [NM_000071](https://www.ncbi.nlm.nih.gov/nuccore/NM_000071) |
| dbSNP | [rs1801181](https://www.ncbi.nlm.nih.gov/snp/rs1801181/) |
| Variant type | single nucleotide variant |
| Location | chr21:43060506-43060506 (GRCh38) |
| ClinVar | [VCV92424](https://www.ncbi.nlm.nih.gov/clinvar/variation/92424/) |

**All HGVS expressions:** `LRG_777:g.20425C>T`, `LRG_777t1:c.1080C>T`, `NC_000021.8:g.44480616G>A`, `NC_000021.9:g.43060506G>A`, `NG_008938.1:g.20425C>T`, `NM_000071.3:c.1080C>T`, `NM_001178008.3:c.1080C>T`, `NM_001178009.3:c.1080C>T`, `NM_001320298.2:c.1080C>T`, `NM_001321072.1:c.765C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 60.9%, eas) — too common for a highly-penetrant pathogenic allele.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -10.297, GERP -2.16 — fast-evolving / accelerated position
- CADD: **PHRED 0.12**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **60.9%** (eas) · FAF95 58.6% · FAF99 57.6% · 1,772/2,908 in the highest group · 15,727/41,226 alleles overall — common (popmax 60.9%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 60.9% | 2 |
| Finnish (not grpmax-eligible) | 52.4% | 2 |
| European (non-Finnish) | 42.3% | 2 |
| Remaining individuals (not grpmax-eligible) | 41.9% | 2 |
| Ashkenazi Jewish (not grpmax-eligible) | 38.1% | 3 |
| Middle Eastern | 35.6% | 3 |
| South Asian | 34.1% | 3 |
| Admixed American | 21.2% | 5 |
| African / African-American | 5.71% | 18 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}


Curated gene–disease validity (ClinGen):

- **classic homocystinuria** — Definitive (AR)

## Protein context {#protein}

Residue **360** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 90.15, 75% of residues very-high.

**28 experimental structure(s)** (PDB): [1JBQ](https://www.rcsb.org/structure/1JBQ), [1M54](https://www.rcsb.org/structure/1M54), [4COO](https://www.rcsb.org/structure/4COO), [4L0D](https://www.rcsb.org/structure/4L0D), [4L27](https://www.rcsb.org/structure/4L27), [4L28](https://www.rcsb.org/structure/4L28) — incl. mutant structure 4L27.

## What this gene does {#gene-function}

*Describes the biological roles of CBS (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CBS's established molecular role includes cystathionine beta-synthase activity.


### Pathways affected {#pathways}

CBS participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cysteine formation from homocysteine](https://reactome.org/content/detail/R-HSA-1614603) | curated |
| [Metabolism of ingested SeMet, Sec, MeSec into H2Se](https://reactome.org/content/detail/R-HSA-2408508) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** cystathionine beta-synthase activity, oxygen binding, enzyme binding, heme binding, pyridoxal phosphate binding, ubiquitin protein ligase binding.

**Biological process:** L-serine metabolic process, L-serine catabolic process, L-cysteine biosynthetic process, L-cysteine catabolic process, DNA protection, L-homocysteine catabolic process.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (18 Benign, 1 Uncertain significance).

**Submission history:** 19 submissions (2013–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2013-04-04 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Natera, Inc. | Benign | no assertion criteria provided | clinical testing | 2020-09-16 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2014-11-24 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2021-04-07 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2025-07-29 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Benign | criteria provided, single submitter | clinical testing | 2017-07-28 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | no assertion criteria provided | clinical testing |  |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-10-04 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2014-03-12 |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-07-14 |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Benign | criteria provided, single submitter | clinical testing | 2025-04-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-28 |
| Genome Diagnostics Laboratory, Amsterdam University Medical Center | Benign | no assertion criteria provided | clinical testing | 2015-09-23 |

## Associated conditions {#conditions}

[classic homocystinuria](https://sugi.bio/atlas/disease/classic-homocystinuria/), [familial thoracic aortic aneurysm and aortic dissection](https://sugi.bio/atlas/disease/familial-thoracic-aortic-aneurysm-and-aortic-dissection/).

**Reported phenotype names (ClinVar):** Classic homocystinuria, not specified, not provided, Familial thoracic aortic aneurysm and aortic dissection, HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED, AllHighlyPenetrant, none provided, Homocystinuria due to Cystathionine Beta-Synthase Deficiency, Homocystinuria due to CBS deficiency, Cystathionine beta-synthase deficiency.

## Similar variants {#similar}

Related CBS variant pages (same residue, condition, or type): [CBS c.1145+1G>A](/variant/cbs-c-1145-plus-1g-a), [CBS c.1223+1G>T](/variant/cbs-c-1223-plus-1g-t), [CBS c.1224-2A>C](/variant/cbs-c-1224-minus-2a-c), [CBS c.1358+1G>A](/variant/cbs-c-1358-plus-1g-a), [CBS c.1359-1G>C](/variant/cbs-c-1359-minus-1g-c), [CBS c.1468-1G>A](/variant/cbs-c-1468-minus-1g-a), [CBS c.1552+1G>A](/variant/cbs-c-1552-plus-1g-a), [CBS c.209+1G>A](/variant/cbs-c-209-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 92424). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*