# NM_006225.4(PLCD1):c.992G>A (p.Arg331Gln)

https://sugi.bio/variant/plcd1-p-arg331gln

## Summary

**PLCD1 p.Arg331Gln (c.992G>A)** is classified **Likely pathogenic** in PLCD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-03). AlphaMissense: likely benign (0.1399); Very rare (popmax 0.0011%, sas).

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1340615883 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the PLCD1 gene that is considered likely disease-causing, 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 | [PLCD1](https://sugi.bio/atlas/gene/PLCD1/) |
| Protein change (HGVS p.) | p.Arg331Gln |
| Coding change (HGVS c.) | c.992G>A |
| MANE Select transcript | [NM_006225](https://www.ncbi.nlm.nih.gov/nuccore/NM_006225) |
| dbSNP | [rs1340615883](https://www.ncbi.nlm.nih.gov/snp/rs1340615883/) |
| Variant type | single nucleotide variant |
| Location | chr3:38010361-38010361 (GRCh38) |
| ClinVar | [VCV2663335](https://www.ncbi.nlm.nih.gov/clinvar/variation/2663335/) |

**All HGVS expressions:** `NC_000003.11:g.38051852C>T`, `NC_000003.12:g.38010361C>T`, `NG_031922.1:g.24303G>A`, `NM_001130964.2:c.1055G>A`, `NM_006225.4:c.992G>A`, `NR_024071.2:n.1142G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1399) — ⚠ discordant with the pathogenic call
- REVEL 0.19 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.645 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.77) — consistent with the pathogenic call
- Conservation: phyloP 3.961, GERP 1.04, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 28.8**. 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 0.87** across the covering region of the MANE Select transcript (38,007,776–38,029,539), spanning 21,763 bp. Chi-square p 2.1e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.77**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.65** (loss), gain 0.04 / loss 0.65. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · FAF95 2.8e-05% · FAF99 1.1e-05% · 1/91,086 in the highest group · 3/1,614,040 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0011% | 91,086 |
| European (non-Finnish) | 0.000169% | 590,009 |

*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}

Residue **331** lies in the pi-plc x-box domain.

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. p.Arg331Gln falls in the pi-plc x-box domain.


### 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 pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-05-03.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-05-03 |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related PLCD1 variant pages (same residue, condition, or type): [PLCD1 p.Arg331Trp](/variant/plcd1-p-arg331trp), [PLCD1 p.Arg530Ter](/variant/plcd1-p-arg530ter), [PLCD1 p.Arg138His](/variant/plcd1-p-arg138his), [PLCD1 p.Arg476His](/variant/plcd1-p-arg476his), [PLCD1 p.Arg60Gln](/variant/plcd1-p-arg60gln), [PLCD1 p.Pro417Arg](/variant/plcd1-p-pro417arg), [PLCD1 p.Ser650Ala](/variant/plcd1-p-ser650ala), [PLCD1 c.1607-42C>T](/variant/plcd1-c-1607-minus-42c-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 2663335). 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.*