# NM_000071.3(CBS):c.1425G>A (p.Pro475=)

https://sugi.bio/variant/cbs-p-pro475

## Summary

**CBS p.Pro475= (c.1425G>A)** is classified **Conflicting classifications of pathogenicity** in CBS (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-31). No allele count reported in gnomAD v4.1 (AN 1,558); Associated with familial thoracic aortic aneurysm and aortic dissection.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs147885808 · 6 submitters · 2 linked conditions · no allele count reported in gnomAD v4.1 (AN 1,558)

## For patients & families {#patients}

This is a change in the CBS gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 6 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.Pro475= |
| Coding change (HGVS c.) | c.1425G>A |
| MANE Select transcript | [NM_000071](https://www.ncbi.nlm.nih.gov/nuccore/NM_000071) |
| dbSNP | [rs147885808](https://www.ncbi.nlm.nih.gov/snp/rs147885808/) |
| Variant type | single nucleotide variant |
| Location | chr21:43058187-43058187 (GRCh38) |
| ClinVar | [VCV413353](https://www.ncbi.nlm.nih.gov/clinvar/variation/413353/) |

**All HGVS expressions:** `LRG_777:g.22744G>A`, `LRG_777t1:c.1425G>A`, `NC_000021.8:g.44478297C>T`, `NC_000021.9:g.43058187C>T`, `NG_008938.1:g.22744G>A`, `NM_000071.3:c.1425G>A`, `NM_001178008.3:c.1425G>A`, `NM_001178009.3:c.1425G>A`, `NM_001320298.2:c.1425G>A`, `NM_001321072.1:c.1110G>A`

## Computational & population evidence {#evidence}

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

- **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 -20, GERP -2.44 — fast-evolving / accelerated position
- CADD: **PHRED 0.099**. 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: **no allele count reported in gnomAD v4.1 (AN 1,558)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 **475** lies in the cbs domain.

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. p.Pro475= falls in the cbs domain.


### 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-31.

**Submitter consensus:** conflicting (5 Likely benign, 1 Uncertain significance).

**Submission history:** 6 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2016-02-22 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2017-11-03 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | criteria provided, single submitter | clinical testing | 2025-06-25 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-31 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-08-29 |

## 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, Classic homocystinuria, not specified, HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED, not provided, AllHighlyPenetrant, none provided, Thoracic aortic aneurysms and dissections, HOMOCYSTINURIA WITH OR WITHOUT RESPONSE TO PYRIDOXINE, Homocystinuria due to Cystathionine Beta-Synthase Deficiency.

## Similar variants {#similar}

Related CBS variant pages (same residue, condition, or type): [CBS p.Pro475Leu](/variant/cbs-p-pro475leu), [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).

### 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 413353). 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.*