# NM_138364.4(PRMT9):c.734_735del (p.Ile245fs)

https://sugi.bio/variant/prmt9-p-ile245fs

## Summary

**PRMT9 p.Ile245fs (c.734_735del)** is classified **Pathogenic** in PRMT9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). Associated with PRMT9-associated neurodevelopmental disorder.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the PRMT9 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to PRMT9-associated neurodevelopmental disorder.

*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 | [PRMT9](https://sugi.bio/atlas/gene/PRMT9/) |
| Protein change (HGVS p.) | p.Ile245fs |
| Coding change (HGVS c.) | c.734_735del |
| MANE Select transcript | [NM_138364](https://www.ncbi.nlm.nih.gov/nuccore/NM_138364) |
| Variant type | Deletion |
| Location | chr4:147672967-147672968 (GRCh38) |
| ClinVar | [VCV4530584](https://www.ncbi.nlm.nih.gov/clinvar/variation/4530584/) |

**All HGVS expressions:** `NC_000004.11:g.148594118_148594119del`, `NC_000004.12:g.147672967_147672968del`, `NG_053105.1:g.16263_16264del`, `NM_001304458.2:c.395_396del`, `NM_001350141.2:c.-681_-680del`, `NM_001350142.2:c.395_396del`, `NM_001350143.2:c.-147_-146del`, `NM_001350144.2:c.-486_-485del`, `NM_138364.4:c.734_735del`

## 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 11.715, GERP 1.74, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.91, pLI 2.4579e-12. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 12**, 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.

*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}

**PRMT9** population constraint: LOEUF 0.91, pLI 2.4579e-12, missense-Z 1.3703. *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 **245** lies in a β-strand; the sam-dependent mtase prmt-type 1 domain.

AlphaFold model confidence (whole protein): pLDDT 86.94, 72% of residues very-high.

**4 experimental structure(s)** (PDB): [6PDM](https://www.rcsb.org/structure/6PDM), [7RBQ](https://www.rcsb.org/structure/7RBQ), [7T39](https://www.rcsb.org/structure/7T39), [9AY9](https://www.rcsb.org/structure/9AY9).

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

*Describes the biological roles of PRMT9 (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:** PRMT9's established molecular role includes protein-arginine N-methyltransferase activity. p.Ile245fs falls in the sam-dependent mtase prmt-type 1 domain.


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

**Molecular function:** protein-arginine N-methyltransferase activity, protein-arginine omega-N symmetric methyltransferase activity.

**Biological process:** mRNA processing.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-02.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics, University of Leipzig Medical Center | pathogenic | criteria provided, single submitter | clinical testing | 2025-10-02 |

## Associated conditions {#conditions}

[PRMT9-associated neurodevelopmental disorder](https://sugi.bio/atlas/disease/prmt9-associated-neurodevelopmental-disorder/).

**Reported phenotype names (ClinVar):** PRMT9-associated neurodevelopmental disorder.

## Similar variants {#similar}

Related PRMT9 variant pages (same residue, condition, or type): [PRMT9 p.Glu264Asp](/variant/prmt9-p-glu264asp), [PRMT9 p.Ile170Thr](/variant/prmt9-p-ile170thr), [PRMT9 p.Trp152Ter](/variant/prmt9-p-trp152ter), [PRMT9 c.(846+1_847-1](/variant/prmt9-c-846-plus-1-847-minus-1), [PRMT9 p.Gln382fs](/variant/prmt9-p-gln382fs), [PRMT9 p.Gly781fs](/variant/prmt9-p-gly781fs), [PRMT9 p.Leu182fs](/variant/prmt9-p-leu182fs), [PRMT9 p.Leu279fs](/variant/prmt9-p-leu279fs).

### 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 4530584). 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.*