# NM_002225.5(IVD):c.693dup (p.Pro232fs)

https://sugi.bio/variant/ivd-p-pro232fs

## Summary

**IVD p.Pro232fs (c.693dup)** is classified **Likely pathogenic** in IVD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-01). No gnomAD frequency available for this variant; Associated with isovaleric acidemia.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2542713682 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the IVD gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to isovaleric acidemia.

*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) | Adolescent, Adult, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | IVD is a diagnostic-grade gene on 12 Genomics England panels |

**Commonly reported features of Isovaleric acidemia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Global developmental delay — Very frequent (99-80%)
- Metabolic acidosis — Very frequent (99-80%)
- Intellectual disability — Frequent (79-30%)
- Seizure — Frequent (79-30%)
- Hypotonia — Frequent (79-30%)
- Lethargy — Frequent (79-30%)
- Failure to thrive — Frequent (79-30%)
- Hyperammonemia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000465/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [IVD](https://sugi.bio/atlas/gene/IVD/) |
| Protein change (HGVS p.) | p.Pro232fs |
| Coding change (HGVS c.) | c.693dup |
| MANE Select transcript | [NM_002225](https://www.ncbi.nlm.nih.gov/nuccore/NM_002225) |
| dbSNP | [rs2542713682](https://www.ncbi.nlm.nih.gov/snp/rs2542713682/) |
| Variant type | Duplication |
| Location | chr15:40412995-40412996 (GRCh38) |
| ClinVar | [VCV1724852](https://www.ncbi.nlm.nih.gov/clinvar/variation/1724852/) |

**All HGVS expressions:** `NC_000015.10:g.40412996dup`, `NC_000015.9:g.40705195dup`, `NG_011986.2:g.12512dup`, `NM_001159508.3:c.603dup`, `NM_001354597.3:c.645dup`, `NM_001354598.3:c.693dup`, `NM_001354599.3:c.780dup`, `NM_001354600.3:c.780dup`, `NM_001354601.3:c.693dup`, `NM_002225.5:c.693dup`, `NR_148925.2:n.1105dup`

## 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 1.521, GERP 0.589, phastCons 1 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.776, pLI 7.3062e-06. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 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 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}

**IVD** population constraint: LOEUF 0.776, pLI 7.3062e-06, missense-Z 1.648. *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):

- **isovaleric acidemia** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 93.25, 91% of residues very-high.

**5 experimental structure(s)** (PDB): [1IVH](https://www.rcsb.org/structure/1IVH), [8SGR](https://www.rcsb.org/structure/8SGR), [9JQ3](https://www.rcsb.org/structure/9JQ3), [9JQ4](https://www.rcsb.org/structure/9JQ4), [9JQ5](https://www.rcsb.org/structure/9JQ5).

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

*Describes the biological roles of IVD (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:** IVD's established molecular role includes 3-methylbutanoyl-CoA dehydrogenase activity. In Reactome, IVD is annotated in disease pathway(s) including **Isovaleric acidemia**.

**Disease mechanism (Reactome):** IVD loss or alteration is curated in [Isovaleric acidemia](https://reactome.org/content/detail/R-HSA-9914355).

### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Isovaleric acidemia](https://reactome.org/content/detail/R-HSA-9914355) | curated |
| [Branched-chain amino acid catabolism](https://reactome.org/content/detail/R-HSA-70895) | curated |

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

**Molecular function:** 3-methylbutanoyl-CoA dehydrogenase activity.

**Biological process:** L-leucine catabolic process, branched-chain amino acid catabolic process, fatty acid beta-oxidation using acyl-CoA dehydrogenase.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-03-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Myriad Genetics, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-03-01 |

## Associated conditions {#conditions}

[isovaleric acidemia](https://sugi.bio/atlas/disease/isovaleric-acidemia/).

**Reported phenotype names (ClinVar):** Isovaleryl-CoA dehydrogenase deficiency, ISOVALERIC ACID CoA DEHYDROGENASE DEFICIENCY, Classic Isovaleric Acidemia, Isovaleric acidemia, IVD DEFICIENCY.

## Similar variants {#similar}

Related IVD variant pages (same residue, condition, or type): [IVD p.Pro291fs](/variant/ivd-p-pro291fs), [IVD p.Ser43fs](/variant/ivd-p-ser43fs), [IVD p.Thr223fs](/variant/ivd-p-thr223fs), [IVD p.Ala218fs](/variant/ivd-p-ala218fs), [IVD p.Ala224fs](/variant/ivd-p-ala224fs), [IVD p.Arg411delinsGlyLeuGlyProAlaArgTer](/variant/ivd-p-arg411delinsglyleuglyproalaargter), [IVD p.Asn249Ter](/variant/ivd-p-asn249ter), [IVD p.Glu143_Ala144insTer](/variant/ivd-p-glu143-ala144inster).

### 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 1724852). 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.*