# NM_000071.3(CBS):c.612G>A (p.Val204=)

https://sugi.bio/variant/cbs-p-val204

## Summary

**CBS p.Val204= (c.612G>A)** is classified **Likely benign** in CBS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-12). Very rare (popmax 0.00121%, nfe); Associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs539670390 · 2 submitters · 2 linked conditions · very rare (popmax 0.00121%, nfe)

## For patients & families {#patients}

This is a change in the CBS gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED.

*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.*

**Support & next steps:** [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.Val204= |
| Coding change (HGVS c.) | c.612G>A |
| MANE Select transcript | [NM_000071](https://www.ncbi.nlm.nih.gov/nuccore/NM_000071) |
| dbSNP | [rs539670390](https://www.ncbi.nlm.nih.gov/snp/rs539670390/) |
| Variant type | single nucleotide variant |
| Location | chr21:43065441-43065441 (GRCh38) |
| ClinVar | [VCV1607700](https://www.ncbi.nlm.nih.gov/clinvar/variation/1607700/) |

**All HGVS expressions:** `LRG_777:g.15490G>A`, `LRG_777t1:c.612G>A`, `NC_000021.8:g.44485551C>T`, `NC_000021.9:g.43065441C>T`, `NG_008938.1:g.15490G>A`, `NM_000071.2:c.612G>A`, `NM_000071.3:c.612G>A`, `NM_001178008.3:c.612G>A`, `NM_001178009.3:c.612G>A`, `NM_001320298.2:c.612G>A`, `NM_001321072.1:c.297G>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 -1.745, GERP -2.46 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 2.586**. 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 **0.00121%** (nfe) · FAF95 0.000322% · FAF99 8.9e-05% · 3/247,746 in the highest group · 4/436,230 alleles overall — very rare (popmax 0.00121%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00406% | 24,652 |
| European (non-Finnish) (grpmax) | 0.00121% | 82,582 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **204** 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-03-12.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2023–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-10-22 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2026-03-12 |

## Associated conditions {#conditions}

[HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED](https://sugi.bio/atlas/disease/hyperhomocysteinemia-thrombotic-cbs-related/), [familial thoracic aortic aneurysm and aortic dissection](https://sugi.bio/atlas/disease/familial-thoracic-aortic-aneurysm-and-aortic-dissection/).

**Reported phenotype names (ClinVar):** HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED, Familial thoracic aortic aneurysm and aortic dissection, Thoracic aortic aneurysms and dissections.

## Similar variants {#similar}

Related CBS variant pages (same residue, condition, or type): [CBS p.Val204Met](/variant/cbs-p-val204met), [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.1552+1G>A](/variant/cbs-c-1552-plus-1g-a), [CBS c.451+1G>T](/variant/cbs-c-451-plus-1g-t), [CBS c.531+1G>A](/variant/cbs-c-531-plus-1g-a), [CBS c.736+2T>G](/variant/cbs-c-736-plus-2t-g).

### 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 1607700). 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.*