# NM_006254.4(PRKCD):c.1051T>G (p.Phe351Val)

https://sugi.bio/variant/prkcd-p-phe351val

## Summary

**PRKCD p.Phe351Val (c.1051T>G)** is classified **Uncertain significance** in PRKCD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-04). AlphaMissense: ambiguous (0.5488); Very rare (popmax 0.00668%, eas); Associated with autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs782444193 · 2 submitters · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 0.00668%, eas)

## For patients & families {#patients}

This is a change in the PRKCD gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, 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.Phe351Val |
| Coding change (HGVS c.) | c.1051T>G |
| MANE Select transcript | [NM_006254](https://www.ncbi.nlm.nih.gov/nuccore/NM_006254) |
| dbSNP | [rs782444193](https://www.ncbi.nlm.nih.gov/snp/rs782444193/) |
| Variant type | single nucleotide variant |
| Location | chr3:53185992-53185992 (GRCh38) |
| ClinVar | [VCV964363](https://www.ncbi.nlm.nih.gov/clinvar/variation/964363/) |

**All HGVS expressions:** `LRG_1327:g.34984T>G`, `LRG_1327t1:c.1051T>G`, `NC_000003.11:g.53220008T>G`, `NC_000003.12:g.53185992T>G`, `NG_033864.2:g.34984T>G`, `NM_001316327.2:c.1051T>G`, `NM_001354676.2:c.1108T>G`, `NM_001354678.2:c.1099T>G`, `NM_001354679.2:c.1051T>G`, `NM_001354680.2:c.1051T>G`, `NM_006254.4:c.1051T>G`, `NM_212539.2:c.1051T>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.5488) — no call either way
- REVEL 0.361 (indeterminate)
- SaProt LLR -10.444 (damaging)
- Conservation: phyloP 6.152, GERP 1.48, phastCons 1 — highly conserved
- CADD: **PHRED 26.0**. 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 1.12** across the covering region of the MANE Select transcript (53,184,955–53,185,992), spanning 1,037 bp. Chi-square p 0.31. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00668%** (eas) · FAF95 0.00177% · FAF99 0.000891% · 3/44,882 in the highest group · 5/1,614,222 alleles overall — very rare (popmax 0.00668%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00668% | 14,961 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,256 |

*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}

Residue **351** lies in the protein kinase domain.

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. p.Phe351Val falls in the protein kinase domain.


### 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-04-04.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2021–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-12-14 |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-04 |

## 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, not provided, none provided.

## Similar variants {#similar}

Related PRKCD variant pages (same residue, condition, or type): [PRKCD p.Phe351=](/variant/prkcd-p-phe351), [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).

### 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 964363). 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.*