# NM_006254.4(PRKCD):c.660C>T (p.Phe220=)

https://sugi.bio/variant/prkcd-p-phe220

## Summary

**PRKCD p.Phe220= (c.660C>T)** is classified **Likely benign** in PRKCD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-03). Absent from gnomAD v4.1; Associated with autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD.

**At a glance:** Likely benign · review: Single submitter · rsID rs2471091199 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PRKCD gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Diagnostic panels | PRKCD is a diagnostic-grade gene on 2 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015987/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PRKCD](https://sugi.bio/atlas/gene/PRKCD/) |
| Protein change (HGVS p.) | p.Phe220= |
| Coding change (HGVS c.) | c.660C>T |
| MANE Select transcript | [NM_006254](https://www.ncbi.nlm.nih.gov/nuccore/NM_006254) |
| dbSNP | [rs2471091199](https://www.ncbi.nlm.nih.gov/snp/rs2471091199/) |
| Variant type | single nucleotide variant |
| Location | chr3:53183454-53183454 (GRCh38) |
| ClinVar | [VCV3006484](https://www.ncbi.nlm.nih.gov/clinvar/variation/3006484/) |

**All HGVS expressions:** `LRG_1327:g.32446C>T`, `LRG_1327t1:c.660C>T`, `NC_000003.11:g.53217470C>T`, `NC_000003.12:g.53183454C>T`, `NG_033864.2:g.32446C>T`, `NM_001316327.2:c.660C>T`, `NM_001354676.2:c.717C>T`, `NM_001354678.2:c.708C>T`, `NM_001354679.2:c.660C>T`, `NM_001354680.2:c.660C>T`, `NM_006254.4:c.660C>T`, `NM_212539.2:c.660C>T`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 2.673, GERP 0.18, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 16.61**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.36 acceptor 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**PRKCD** population constraint: LOEUF 0.344, pLI 1, missense-Z 3.8706. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **systemic lupus erythematosus** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 81.29, 46% of residues very-high.

**2 experimental structure(s)** (PDB): [1YRK](https://www.rcsb.org/structure/1YRK), [2YUU](https://www.rcsb.org/structure/2YUU).

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

*Describes the biological roles of PRKCD (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:** PRKCD's established molecular role includes protein kinase activity.


### Pathways affected {#pathways}

PRKCD participates in **14 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Apoptotic cleavage of cellular proteins](https://reactome.org/content/detail/R-HSA-111465) | curated |
| [CLEC7A (Dectin-1) signaling](https://reactome.org/content/detail/R-HSA-5607764) | curated |
| [Calmodulin induced events](https://reactome.org/content/detail/R-HSA-111933) | curated |
| [DAG and IP3 signaling](https://reactome.org/content/detail/R-HSA-1489509) | curated |
| [Effects of PIP2 hydrolysis](https://reactome.org/content/detail/R-HSA-114508) | curated |
| [HuR (ELAVL1) binds and stabilizes mRNA](https://reactome.org/content/detail/R-HSA-450520) | curated |
| [Interferon gamma signaling](https://reactome.org/content/detail/R-HSA-877300) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [RHO GTPases Activate NADPH Oxidases](https://reactome.org/content/detail/R-HSA-5668599) | curated |
| [Role of phospholipids in phagocytosis](https://reactome.org/content/detail/R-HSA-2029485) | curated |
| [SHC1 events in ERBB2 signaling](https://reactome.org/content/detail/R-HSA-1250196) | curated |
| [VEGFR2 mediated cell proliferation](https://reactome.org/content/detail/R-HSA-5218921) | curated |
| [G alpha (z) signalling events](https://reactome.org/content/detail/R-HSA-418597) | electronic |
| [KEAP1-NFE2L2 pathway](https://reactome.org/content/detail/R-HSA-9755511) | electronic |

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

**Molecular function:** protein kinase activity, protein serine/threonine kinase activity, calcium,diacylglycerol-dependent serine/threonine kinase activity, diacylglycerol-dependent, calcium-independent serine/threonine kinase activity, enzyme activator activity, enzyme binding.

**Biological process:** protein phosphorylation, apoptotic process, DNA damage response, peptidyl-serine phosphorylation, peptidyl-threonine phosphorylation, termination of signal transduction.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-03.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-10-03 |

## Associated conditions {#conditions}

[autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD](https://sugi.bio/atlas/disease/autoimmune-lymphoproliferative-syndrome-type-iii-caused-by-mutation-in-prkcd/).

**Reported phenotype names (ClinVar):** Autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD.

## Similar variants {#similar}

Related PRKCD variant pages (same residue, condition, or type): [PRKCD c.787+4C>T](/variant/prkcd-c-787-plus-4c-t), [PRKCD p.Ala195Val](/variant/prkcd-p-ala195val), [PRKCD p.Ala212Val](/variant/prkcd-p-ala212val), [PRKCD p.Ala404Gly](/variant/prkcd-p-ala404gly), [PRKCD p.Arg273Trp](/variant/prkcd-p-arg273trp), [PRKCD p.Arg40His](/variant/prkcd-p-arg40his), [PRKCD p.Arg444Cys](/variant/prkcd-p-arg444cys), [PRKCD p.Arg569His](/variant/prkcd-p-arg569his).

### 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 3006484). 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.*