# NM_006225.4(PLCD1):c.843G>A (p.Ser281=)

https://sugi.bio/variant/plcd1-p-ser281

## Summary

**PLCD1 p.Ser281= (c.843G>A)** is classified **Likely benign** in PLCD1 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2019-10-01). Ultra-rare (popmax 0.0165%, mid); Associated with PLCD1-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs138396052 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the PLCD1 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to PLCD1-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 | [PLCD1](https://sugi.bio/atlas/gene/PLCD1/) |
| Protein change (HGVS p.) | p.Ser281= |
| Coding change (HGVS c.) | c.843G>A |
| MANE Select transcript | [NM_006225](https://www.ncbi.nlm.nih.gov/nuccore/NM_006225) |
| dbSNP | [rs138396052](https://www.ncbi.nlm.nih.gov/snp/rs138396052/) |
| Variant type | single nucleotide variant |
| Location | chr3:38010510-38010510 (GRCh38) |
| ClinVar | [VCV3040855](https://www.ncbi.nlm.nih.gov/clinvar/variation/3040855/) |

**All HGVS expressions:** `NC_000003.11:g.38052001C>T`, `NC_000003.12:g.38010510C>T`, `NG_031922.1:g.24154G>A`, `NM_001130964.2:c.906G>A`, `NM_006225.4:c.843G>A`, `NR_024071.2:n.993G>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.25) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -11.394, GERP -4.26 — fast-evolving / accelerated position
- CADD: **PHRED 4.438**. 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 deltas (raw): acceptor loss **0.02**, donor loss **0.00**, acceptor gain **0.25**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.25**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 0.00944% · FAF99 0.00888% · 1/6,078 in the highest group · 148/1,614,004 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,078 |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,925 |
| European (non-Finnish) | 0.011% | 9,077 |
| Finnish (not grpmax-eligible) | 0.00625% | 16,005 |
| South Asian | 0.00329% | 30,363 |
| African / African-American | 0.00267% | 37,465 |
| East Asian | 0.00223% | 44,880 |

*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}

**PLCD1** population constraint: LOEUF 0.954, pLI 1.642e-19, missense-Z 1.9691. *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 89.31, 65% of residues very-high.

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

*Describes the biological roles of PLCD1 (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:** PLCD1's established molecular role includes phosphatidylinositol-4,5-bisphosphate phospholipase C activity.


### Pathways affected {#pathways}

PLCD1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of IP3 and IP4 in the cytosol](https://reactome.org/content/detail/R-HSA-1855204) | curated |

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

**Molecular function:** phosphatidylinositol-4,5-bisphosphate phospholipase C activity, phosphatidylinositol-4,5-bisphosphate binding, GTPase activating protein binding.

**Biological process:** phosphatidylinositol metabolic process, phospholipase C/protein kinase C signal transduction.

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-10-01.

**Submitter consensus:** unanimous (1/1 Likely benign).

**Submission history:** 2 submissions (2019); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-10-01 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |

## Associated conditions {#conditions}

[PLCD1-related disorder](https://sugi.bio/atlas/disease/plcd1-related-disorder/).

**Reported phenotype names (ClinVar):** PLCD1-related disorder, Ovarian serous cystadenocarcinoma, PLCD1-related condition.

## Similar variants {#similar}

Related PLCD1 variant pages (same residue, condition, or type): [PLCD1 p.Ser281Leu](/variant/plcd1-p-ser281leu), [PLCD1 p.Ala553Thr](/variant/plcd1-p-ala553thr), [PLCD1 p.Glu462Lys](/variant/plcd1-p-glu462lys), [PLCD1 c.429-5C>T](/variant/plcd1-c-429-minus-5c-t), [PLCD1 c.993-4G>A](/variant/plcd1-c-993-minus-4g-a), [PLCD1 c.993-5C>T](/variant/plcd1-c-993-minus-5c-t), [PLCD1 p.Ala249=](/variant/plcd1-p-ala249), [PLCD1 p.His546=](/variant/plcd1-p-his546).

### 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 3040855). 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.*