# NM_022114.4(PRDM16):c.1496_1497del (p.Pro499fs)

https://sugi.bio/variant/prdm16-p-pro499fs

## Summary

**PRDM16 p.Pro499fs (c.1496_1497del)** is classified **Uncertain significance** in PRDM16 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-22). No gnomAD frequency available for this variant; Associated with left ventricular noncompaction 8.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2523881887 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PRDM16 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to left ventricular noncompaction 8.

*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 dominant, Autosomal recessive, Mitochondrial inheritance |
| Age of onset (of this condition) | All ages |
| Diagnostic panels | PRDM16 is a diagnostic-grade gene on 4 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015952/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PRDM16](https://sugi.bio/atlas/gene/PRDM16/) |
| Protein change (HGVS p.) | p.Pro499fs |
| Coding change (HGVS c.) | c.1496_1497del |
| MANE Select transcript | [NM_022114](https://www.ncbi.nlm.nih.gov/nuccore/NM_022114) |
| dbSNP | [rs2523881887](https://www.ncbi.nlm.nih.gov/snp/rs2523881887/) |
| Variant type | Deletion |
| Location | chr1:3411692-3411693 (GRCh38) |
| ClinVar | [VCV2866784](https://www.ncbi.nlm.nih.gov/clinvar/variation/2866784/) |

**All HGVS expressions:** `NC_000001.10:g.3328257_3328258del`, `NC_000001.11:g.3411693_3411694del`, `NG_029576.2:g.347516_347517del`, `NM_022114.4:c.1496_1497del`, `NM_199454.3:c.1496_1497del`

## 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 2.848, GERP -3.18, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.304, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 9 of 17**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**PRDM16** population constraint: LOEUF 0.304, pLI 1, missense-Z 1.5748. *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):

- **dilated cardiomyopathy** — Strong (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 51.73, 0% of residues very-high.

**2 experimental structure(s)** (PDB): [2N1I](https://www.rcsb.org/structure/2N1I), [6BW4](https://www.rcsb.org/structure/6BW4).

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

*Describes the biological roles of PRDM16 (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:** PRDM16's established molecular role includes transcription cis-regulatory region binding.


### Pathways affected {#pathways}

PRDM16 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [PKMTs methylate histone lysines](https://reactome.org/content/detail/R-HSA-3214841) | curated |
| [Transcriptional regulation of brown and beige adipocyte differentiation by EBF2](https://reactome.org/content/detail/R-HSA-9844594) | electronic |

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

**Molecular function:** transcription cis-regulatory region binding, DNA-binding transcription repressor activity, RNA polymerase II-specific, sequence-specific DNA binding, DNA-binding transcription factor binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, negative regulation of transforming growth factor beta receptor signaling pathway, negative regulation of granulocyte differentiation, negative regulation of DNA-templated transcription, positive regulation of DNA-templated transcription, protein maturation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-05-22.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-22 |

## Associated conditions {#conditions}

[left ventricular noncompaction 8](https://sugi.bio/atlas/disease/left-ventricular-noncompaction-8/).

**Reported phenotype names (ClinVar):** Left ventricular noncompaction 8.

## Similar variants {#similar}

Related PRDM16 variant pages (same residue, condition, or type): [PRDM16 p.Pro499Ser](/variant/prdm16-p-pro499ser), [PRDM16 p.Glu487fs](/variant/prdm16-p-glu487fs), [PRDM16 p.Lys578del](/variant/prdm16-p-lys578del), [PRDM16 c.884+39_884+69del](/variant/prdm16-c-884-plus-39-884-plus-69del), [PRDM16 c.884+8_884+38del](/variant/prdm16-c-884-plus-8-884-plus-38del), [PRDM16 p.Arg812fs](/variant/prdm16-p-arg812fs), [PRDM16 p.Leu1048fs](/variant/prdm16-p-leu1048fs), [PRDM16 c.2414_2603+44del](/variant/prdm16-c-2414-2603-plus-44del).

### 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 2866784). 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.*