# NM_000071.3(CBS):c.341C>T (p.Ala114Val)

https://sugi.bio/variant/cbs-p-ala114val

## Summary

**CBS p.Ala114Val (c.341C>T)** is classified **Pathogenic/Likely pathogenic** in CBS (ClinVar, Multiple submitters, 24 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.2866); Ultra-rare (popmax 0.0155%, eas); Associated with CBS-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs121964964 · 24 submitters · 4 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0155%, eas)

## For patients & families {#patients}

This is a change in the CBS gene that is considered likely disease-causing, submitted by 24 submitters, and is linked to CBS-related disorder.

*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.Ala114Val |
| Coding change (HGVS c.) | c.341C>T |
| MANE Select transcript | [NM_000071](https://www.ncbi.nlm.nih.gov/nuccore/NM_000071) |
| dbSNP | [rs121964964](https://www.ncbi.nlm.nih.gov/snp/rs121964964/) |
| Variant type | single nucleotide variant |
| Location | chr21:43066353-43066353 (GRCh38) |
| ClinVar | [VCV119](https://www.ncbi.nlm.nih.gov/clinvar/variation/119/) |

**All HGVS expressions:** `LRG_777:g.14578C>T`, `LRG_777t1:c.341C>T`, `NC_000021.8:g.44486463G>A`, `NC_000021.9:g.43066353G>A`, `NG_008938.1:g.14578C>T`, `NM_000071.3:c.341C>T`, `NM_001178008.3:c.341C>T`, `NM_001178009.3:c.341C>T`, `NM_001320298.2:c.341C>T`, `NM_001321072.1:c.26C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.2866) — ⚠ discordant with the pathogenic call
- REVEL 0.88 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -10.322 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 7.23, GERP 1.47, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.2**. 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 0.63** across the covering region of the MANE Select transcript (43,066,348–43,072,193), spanning 5,845 bp. Chi-square p 0.12. 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 **0.0155%** (eas) · FAF95 0.0106% · FAF99 0.00972% · 6/38,706 in the highest group · 87/813,628 alleles overall — ultra-rare (popmax 0.0155%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0155% | 6,451 |
| Admixed American | 0.0153% | 6,521 |
| European (non-Finnish) | 0.0131% | 7,630 |
| Remaining individuals (not grpmax-eligible) | 0.00823% | 12,145 |

*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 **114** lies in a β-strand; a UniProt-annotated variant site (in cbsd; mild form; when linked with w-58 severe form; decreased cystathionine beta-synthase activity; decreases homotetramer formation by promoting formation of larger aggregates).

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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-01.

**Submitter consensus:** conflicting (19 Pathogenic, 4 Likely pathogenic, 1 not provided).

**Submission history:** 24 submissions (1993–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Centre for Mendelian Genomics, University Medical Centre Ljubljana | Pathogenic | criteria provided, single submitter | clinical testing | 2019-08-16 |
| Mayo Clinic Laboratories, Mayo Clinic | Pathogenic | criteria provided, single submitter | clinical testing | 2020-05-21 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2020-10-15 |
| Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Pathogenic | criteria provided, single submitter | clinical testing | 2023-02-14 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-11-28 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1993-06-01 |
| Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Likely pathogenic | criteria provided, single submitter | reference population | 2016-03-18 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2016-01-26 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2018-10-31 |
| Institute of Human Genetics, University of Leipzig Medical Center | Pathogenic | criteria provided, single submitter | clinical testing | 2020-03-01 |
| PreventionGenetics, part of Exact Sciences | Pathogenic | no assertion criteria provided | clinical testing | 2023-12-24 |
| Genomic Research Center, Shahid Beheshti University of Medical Sciences | Pathogenic | criteria provided, single submitter | clinical testing | 2017-12-03 |
| Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Pathogenic | criteria provided, single submitter | clinical testing | 2020-10-23 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-05 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-24 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-11-24 |
| Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Pathogenic | criteria provided, single submitter | curation | 2024-02-01 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-30 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Pathogenic | criteria provided, single submitter | research | 2023-03-13 |
| Counsyl | Likely pathogenic | no assertion criteria provided | clinical testing | 2017-03-01 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-02-01 |
| Dasa | Pathogenic | criteria provided, single submitter | clinical testing | 2025-04-18 |
| GenomeConnect, ClinGen | not provided | no classification provided | phenotyping only |  |

## Associated conditions {#conditions}

[CBS-related disorder](https://sugi.bio/atlas/disease/cbs-related-disorder/), [homocystinuria](https://sugi.bio/atlas/disease/homocystinuria/), [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):** CBS-related disorder, Homocystinuria, pyridoxine-responsive, not provided, Classic homocystinuria, Homocystinuria, HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED, Familial thoracic aortic aneurysm and aortic dissection, CBS-related condition, none provided, Thoracic aortic aneurysms and dissections.

## Same-residue context {#hotspot}

Residue **114** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CBS p.Ala114Ser](/variant/cbs-p-ala114ser). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CBS variant pages (same residue, condition, or type): [CBS p.Ala114=](/variant/cbs-p-ala114), [CBS p.Ala114Ser](/variant/cbs-p-ala114ser), [CBS p.Ala114Thr](/variant/cbs-p-ala114thr), [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 119). 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.*