# NM_000071.3(CBS):c.394C>A (p.Arg132Ser)

https://sugi.bio/variant/cbs-p-arg132ser

## Summary

**CBS p.Arg132Ser (c.394C>A)** is classified **Uncertain significance** in CBS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-24). AlphaMissense: likely benign (0.2747); Ultra-rare (popmax 0.0125%, afr); Associated with familial thoracic aortic aneurysm and aortic dissection.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs140002610 · 3 submitters · 2 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0125%, afr)

## For patients & families {#patients}

This is a change in the CBS gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to familial thoracic aortic aneurysm and aortic dissection.

*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 dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CBS is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Familial thoracic aortic aneurysm and aortic dissection** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Cutis marmorata — Very frequent (99-80%)
- Abnormality of connective tissue — Very frequent (99-80%)
- Cystic medial necrosis of the aorta — Very frequent (99-80%)
- Abnormality iris morphology — Frequent (79-30%)
- Hypertension — Frequent (79-30%)
- Cardiomegaly — Frequent (79-30%)
- Aortic regurgitation — Frequent (79-30%)
- Coronaryartery atherosclerosis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002249/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.Arg132Ser |
| Coding change (HGVS c.) | c.394C>A |
| MANE Select transcript | [NM_000071](https://www.ncbi.nlm.nih.gov/nuccore/NM_000071) |
| dbSNP | [rs140002610](https://www.ncbi.nlm.nih.gov/snp/rs140002610/) |
| Variant type | single nucleotide variant |
| Location | chr21:43066300-43066300 (GRCh38) |
| ClinVar | [VCV263891](https://www.ncbi.nlm.nih.gov/clinvar/variation/263891/) |

**All HGVS expressions:** `LRG_777:g.14631C>A`, `LRG_777t1:c.394C>A`, `NC_000021.8:g.44486410G>T`, `NC_000021.9:g.43066300G>T`, `NG_008938.1:g.14631C>A`, `NM_000071.3:c.394C>A`, `NM_001178008.3:c.394C>A`, `NM_001178009.3:c.394C>A`, `NM_001320298.2:c.394C>A`, `NM_001321072.1:c.79C>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.2747)
- REVEL 0.585 (indeterminate)
- SaProt LLR -10.175 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL makes no call
- Conservation: phyloP 2.814, GERP 0.198, phastCons 0.999 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.0**. 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.*
- Regional missense constraint: **o/e 0.24** across the covering region of the MANE Select transcript (43,065,254–43,066,300), spanning 1,046 bp — the region is depleted of missense variation. Chi-square p 7.5e-10. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.0125%** (afr) · FAF95 0.00421% · FAF99 0.00256% · 4/32,000 in the highest group · 5/1,044,314 alleles overall — ultra-rare (popmax 0.0125%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0125% | 8,000 |
| European (non-Finnish) | 0.000137% | 727,754 |

*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 **132** 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-02-24.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2015–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2015-02-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-24 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2019-10-28 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Familial thoracic aortic aneurysm and aortic dissection, HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED, Classic homocystinuria, Thoracic aortic aneurysms and dissections, Homocystinuria due to Cystathionine Beta-Synthase Deficiency, Homocystinuria due to CBS deficiency, Cystathionine beta-synthase deficiency, CBS deficiency, HOMOCYSTINURIA WITH OR WITHOUT RESPONSE TO PYRIDOXINE.

## Similar variants {#similar}

Related CBS variant pages (same residue, condition, or type): [CBS p.Arg132His](/variant/cbs-p-arg132his), [CBS p.Arg132=](/variant/cbs-p-arg132), [CBS p.Arg132Cys](/variant/cbs-p-arg132cys), [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).

### 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 263891). 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.*