# NM_152719.3(CBY2):c.151C>T (p.Pro51Ser)

https://sugi.bio/variant/cby2-p-pro51ser

## Summary

**CBY2 p.Pro51Ser (c.151C>T)** is classified **Uncertain significance** in CBY2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-01). AlphaMissense: likely benign (0.1732); Very rare (popmax 0.005%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs763800825 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.005%, amr)

## For patients & families {#patients}

This is a change in the CBY2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [CBY2](https://sugi.bio/atlas/gene/CBY2/) |
| Protein change (HGVS p.) | p.Pro51Ser |
| Coding change (HGVS c.) | c.151C>T |
| MANE Select transcript | [NM_152719](https://www.ncbi.nlm.nih.gov/nuccore/NM_152719) |
| dbSNP | [rs763800825](https://www.ncbi.nlm.nih.gov/snp/rs763800825/) |
| Variant type | single nucleotide variant |
| Location | chr13:45702850-45702850 (GRCh38) |
| ClinVar | [VCV2463871](https://www.ncbi.nlm.nih.gov/clinvar/variation/2463871/) |

**All HGVS expressions:** `NC_000013.10:g.46276985C>T`, `NC_000013.11:g.45702850C>T`, `NM_001286341.2:c.75+385C>T`, `NM_001286342.2:c.-34+335C>T`, `NM_152719.3:c.151C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1732)
- REVEL 0.124 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.189 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.705, GERP 0.504, phastCons 0.986 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 19.34**. 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 1.09** across the covering region of the MANE Select transcript (45,702,391–45,714,369), spanning 11,978 bp. Chi-square p 0.035. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.26 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.005%** (amr) · FAF95 0.00133% · FAF99 0.000719% · 3/59,994 in the highest group · 21/1,610,824 alleles overall — very rare (popmax 0.005%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.005% | 19,998 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,394 |
| European (non-Finnish) | 0.00144% | 69,244 |

*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}

**CBY2** population constraint: LOEUF 1.393, pLI 5.721e-10, missense-Z -1.0511; ClinGen dosage — haploinsufficiency 40, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 63.75, 25% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of CBY2 (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:** CBY2's established molecular role includes identical protein binding.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** identical protein binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-03-01.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-03-01 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CBY2 variant pages (same residue, condition, or type): [CBY2 p.Ala163Thr](/variant/cby2-p-ala163thr), [CBY2 p.Ala205Asp](/variant/cby2-p-ala205asp), [CBY2 p.Ala214Thr](/variant/cby2-p-ala214thr), [CBY2 p.Ala214Val](/variant/cby2-p-ala214val), [CBY2 p.Ala224Glu](/variant/cby2-p-ala224glu), [CBY2 p.Ala269Val](/variant/cby2-p-ala269val), [CBY2 p.Ala76Thr](/variant/cby2-p-ala76thr), [CBY2 p.Arg141His](/variant/cby2-p-arg141his).

### 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 2463871). 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.*