# NM_021619.3(PRDM12):c.578dup (p.Pro194fs)

https://sugi.bio/variant/prdm12-p-pro194fs

## Summary

**PRDM12 p.Pro194fs (c.578dup)** is classified **Pathogenic** in PRDM12 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-30). No gnomAD frequency available for this variant; Associated with congenital insensitivity to pain-hypohidrosis syndrome.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2490743581 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PRDM12 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to congenital insensitivity to pain-hypohidrosis syndrome.

*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 |
| Age of onset (of this condition) | Neonatal |
| Diagnostic panels | PRDM12 is a diagnostic-grade gene on 6 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017866/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PRDM12](https://sugi.bio/atlas/gene/PRDM12/) |
| Protein change (HGVS p.) | p.Pro194fs |
| Coding change (HGVS c.) | c.578dup |
| MANE Select transcript | [NM_021619](https://www.ncbi.nlm.nih.gov/nuccore/NM_021619) |
| dbSNP | [rs2490743581](https://www.ncbi.nlm.nih.gov/snp/rs2490743581/) |
| Variant type | Duplication |
| Location | chr9:130678533-130678534 (GRCh38) |
| ClinVar | [VCV2706647](https://www.ncbi.nlm.nih.gov/clinvar/variation/2706647/) |

**All HGVS expressions:** `NC_000009.11:g.133553923dup`, `NC_000009.12:g.130678536dup`, `NG_053081.1:g.18943dup`, `NM_021619.3:c.578dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 7.789, GERP 2.39, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.153, pLI 2.3682e-05. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 5**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication 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}

**PRDM12** population constraint: LOEUF 1.153, pLI 2.3682e-05, missense-Z 0.24745. *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 **194** lies in the set domain.

AlphaFold model confidence (whole protein): pLDDT 64.81, 12% of residues very-high.

**1 experimental structure(s)** (PDB): [3EP0](https://www.rcsb.org/structure/3EP0).

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

*Describes the biological roles of PRDM12 (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:** PRDM12's established molecular role includes histone chaperone activity. p.Pro194fs falls in the set domain.


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

**Molecular function:** histone chaperone activity, histone methyltransferase binding.

**Biological process:** protein methylation, sensory perception of pain, neuron projection development, detection of temperature stimulus involved in sensory perception of pain.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-12-30.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-30 |

## Associated conditions {#conditions}

[congenital insensitivity to pain-hypohidrosis syndrome](https://sugi.bio/atlas/disease/congenital-insensitivity-to-pain-hypohidrosis-syndrome/).

**Reported phenotype names (ClinVar):** Congenital insensitivity to pain-hypohidrosis syndrome, HSAN VIII, Neuropathy, hereditary sensory and autonomic, type VIII.

## Similar variants {#similar}

Related PRDM12 variant pages (same residue, condition, or type): [PRDM12 p.Ala339_Pro340insHisSerProAlaLeuProAla](/variant/prdm12-p-ala339-pro340inshisserproalaleuproala), [PRDM12 p.Ala329fs](/variant/prdm12-p-ala329fs), [PRDM12 p.Gln331_Leu337dup](/variant/prdm12-p-gln331-leu337dup), [PRDM12 p.His333_Ala339dup](/variant/prdm12-p-his333-ala339dup), [PRDM12 p.Pro345_Ala346dup](/variant/prdm12-p-pro345-ala346dup), [PRDM12 p.Pro345_Ala348dup](/variant/prdm12-p-pro345-ala348dup), [PRDM12 p.Ser256_Arg263dup](/variant/prdm12-p-ser256-arg263dup), [PRDM12 c.682+19dup](/variant/prdm12-c-682-plus-19dup).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 2706647). 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.*