# NM_000071.3(CBS):c.1064C>T (p.Ala355Val)

https://sugi.bio/variant/cbs-p-ala355val

## Summary

**CBS p.Ala355Val (c.1064C>T)** is classified **Conflicting classifications of pathogenicity** in CBS (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-05-21). AlphaMissense: likely benign (0.1293); No allele count reported in gnomAD v4.1 (AN 46,692); Associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs772384826 · 4 submitters · 2 linked conditions · AlphaMissense likely benign · no allele count reported in gnomAD v4.1 (AN 46,692)

## 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 4 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.Ala355Val |
| Coding change (HGVS c.) | c.1064C>T |
| MANE Select transcript | [NM_000071](https://www.ncbi.nlm.nih.gov/nuccore/NM_000071) |
| dbSNP | [rs772384826](https://www.ncbi.nlm.nih.gov/snp/rs772384826/) |
| Variant type | single nucleotide variant |
| Location | chr21:43060522-43060522 (GRCh38) |
| ClinVar | [VCV499847](https://www.ncbi.nlm.nih.gov/clinvar/variation/499847/) |

**All HGVS expressions:** `LRG_777:g.20409C>T`, `NC_000021.8:g.44480632G>A`, `NC_000021.9:g.43060522G>A`, `NG_008938.1:g.20409C>T`, `NM_000071.3:c.1064C>T`, `NM_001178008.3:c.1064C>T`, `NM_001178009.3:c.1064C>T`, `NM_001320298.2:c.1064C>T`, `NM_001321072.1:c.749C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1293)
- REVEL 0.442 (indeterminate)
- SaProt LLR -14.313 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL makes no call
- Conservation: phyloP 9.491, GERP 0.043, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 19.0**. 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 0.00** across the covering region of the MANE Select transcript (43,053,883–43,065,253), spanning 11,370 bp — the region is depleted of missense variation. Chi-square p 6.7e-07. 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: **no allele count reported in gnomAD v4.1 (AN 46,692)** — 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 **355** lies in an α-helix; a UniProt-annotated variant site (in cbsd).

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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-05-21.

**Submitter consensus:** conflicting (2 Uncertain significance, 2 Likely pathogenic).

**Submission history:** 4 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-05 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-01-10 |
| Myriad Genetics, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-05-21 |
| CeGaT Center for Human Genetics Tuebingen | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-05-01 |

## Associated conditions {#conditions}

[HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED](https://sugi.bio/atlas/disease/hyperhomocysteinemia-thrombotic-cbs-related/), [classic homocystinuria](https://sugi.bio/atlas/disease/classic-homocystinuria/).

**Reported phenotype names (ClinVar):** HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED, not provided, Classic homocystinuria, none provided, Homocystinuria due to Cystathionine Beta-Synthase Deficiency, HOMOCYSTINURIA WITH OR WITHOUT RESPONSE TO PYRIDOXINE, Homocystinuria due to CBS deficiency, Cystathionine beta-synthase deficiency, CBS deficiency.

## Same-residue context {#hotspot}

Residue **355** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CBS p.Ala355Pro](/variant/cbs-p-ala355pro). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CBS variant pages (same residue, condition, or type): [CBS p.Ala355=](/variant/cbs-p-ala355), [CBS p.Ala355Pro](/variant/cbs-p-ala355pro), [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).

### 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 499847). 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.*