# NM_000932.5(PLCB3):c.1336C>T (p.Pro446Ser)

https://sugi.bio/variant/plcb3-p-pro446ser

## Summary

**PLCB3 p.Pro446Ser (c.1336C>T)** is classified **Uncertain significance** in PLCB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely benign (0.1975); Very rare (popmax 0.00133%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the PLCB3 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 | [PLCB3](https://sugi.bio/atlas/gene/PLCB3/) |
| Protein change (HGVS p.) | p.Pro446Ser |
| Coding change (HGVS c.) | c.1336C>T |
| MANE Select transcript | [NM_000932](https://www.ncbi.nlm.nih.gov/nuccore/NM_000932) |
| Variant type | single nucleotide variant |
| Location | chr11:64258967-64258967 (GRCh38) |
| ClinVar | [VCV4138631](https://www.ncbi.nlm.nih.gov/clinvar/variation/4138631/) |

**All HGVS expressions:** `NC_000011.10:g.64258967C>T`, `NC_000011.9:g.64026439C>T`, `NM_000932.5:c.1336C>T`, `NM_001184883.2:c.1135C>T`, `NM_001316314.3:c.1336C>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** (0.1975)
- REVEL 0.346 (indeterminate)
- SaProt LLR -7.312 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 7.642, GERP 2, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 29.5**. 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 0.55** across the covering region of the MANE Select transcript (64,256,757–64,259,185), spanning 2,428 bp. Chi-square p 2.1e-11. 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, Δ0.87 donor gain), 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 **0.00133%** (afr) · FAF95 7.9e-05% · FAF99 5.4e-05% · 1/75,028 in the highest group · 6/1,613,972 alleles overall — very rare (popmax 0.00133%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,508 |
| African / African-American (grpmax) | 0.00133% | 75,028 |
| European (non-Finnish) | 0.000339% | 294,998 |

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}

**PLCB3** population constraint: LOEUF 0.468, pLI 0.99465, missense-Z 3.7091. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **446** lies in the pi-plc x-box domain.

AlphaFold model confidence (whole protein): pLDDT 83.47, 64% of residues very-high.

**13 experimental structure(s)** (PDB): [4GNK](https://www.rcsb.org/structure/4GNK), [4QJ3](https://www.rcsb.org/structure/4QJ3), [4QJ4](https://www.rcsb.org/structure/4QJ4), [4QJ5](https://www.rcsb.org/structure/4QJ5), [7SQ2](https://www.rcsb.org/structure/7SQ2), [8EMV](https://www.rcsb.org/structure/8EMV).

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

*Describes the biological roles of PLCB3 (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:** PLCB3's established molecular role includes phosphatidylinositol-4,5-bisphosphate phospholipase C activity. p.Pro446Ser falls in the pi-plc x-box domain.


### Pathways affected {#pathways}

PLCB3 participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Ca2+ pathway](https://reactome.org/content/detail/R-HSA-4086398) | curated |
| [G beta:gamma signalling through PLC beta](https://reactome.org/content/detail/R-HSA-418217) | curated |
| [Presynaptic function of Kainate receptors](https://reactome.org/content/detail/R-HSA-500657) | curated |
| [Synthesis of IP3 and IP4 in the cytosol](https://reactome.org/content/detail/R-HSA-1855204) | curated |
| [Acetylcholine regulates insulin secretion](https://reactome.org/content/detail/R-HSA-399997) | electronic |
| [Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion](https://reactome.org/content/detail/R-HSA-434316) | electronic |
| [G alpha (q) signalling events](https://reactome.org/content/detail/R-HSA-416476) | electronic |
| [PLC beta mediated events](https://reactome.org/content/detail/R-HSA-112043) | electronic |

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

**Molecular function:** phosphatidylinositol-4,5-bisphosphate phospholipase C activity, calmodulin binding, cadherin binding, molecular adaptor activity, molecular function activator activity.

**Biological process:** regulation of systemic arterial blood pressure, phospholipase C-activating G protein-coupled receptor signaling pathway, phospholipase C-activating serotonin receptor signaling pathway, phosphatidylinositol metabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-26.

**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 | 2025-08-26 |

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

## Similar variants {#similar}

Related PLCB3 variant pages (same residue, condition, or type): [PLCB3 p.Ser1107Leu](/variant/plcb3-p-ser1107leu), [PLCB3 c.2038+7C>A](/variant/plcb3-c-2038-plus-7c-a), [PLCB3 c.99+8C>T](/variant/plcb3-c-99-plus-8c-t), [PLCB3 p.Glu1023Asp](/variant/plcb3-p-glu1023asp), [PLCB3 p.Glu60=](/variant/plcb3-p-glu60), [PLCB3 p.Pro171=](/variant/plcb3-p-pro171), [PLCB3 p.Ser845Leu](/variant/plcb3-p-ser845leu), [PLCB3 p.Thr158Met](/variant/plcb3-p-thr158met).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 4138631). 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.*