# NM_001002294.3(FMO3):c.839_842dup (p.Pro282fs)

https://sugi.bio/variant/fmo3-p-pro282fs

## Summary

**FMO3 p.Pro282fs (c.839_842dup)** is classified **Pathogenic** in FMO3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-10). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2526352822 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the FMO3 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter.

*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 | [FMO3](https://sugi.bio/atlas/gene/FMO3/) |
| Protein change (HGVS p.) | p.Pro282fs |
| Coding change (HGVS c.) | c.839_842dup |
| MANE Select transcript | [NM_001002294](https://www.ncbi.nlm.nih.gov/nuccore/NM_001002294) |
| dbSNP | [rs2526352822](https://www.ncbi.nlm.nih.gov/snp/rs2526352822/) |
| Variant type | Duplication |
| Location | chr1:171114015-171114016 (GRCh38) |
| ClinVar | [VCV2863131](https://www.ncbi.nlm.nih.gov/clinvar/variation/2863131/) |

**All HGVS expressions:** `NC_000001.10:g.171083158_171083161dup`, `NC_000001.11:g.171114018_171114021dup`, `NG_012690.1:g.28141_28144dup`, `NG_012690.2:g.28115_28118dup`, `NM_001002294.3:c.839_842dup`, `NM_001319173.2:c.779_782dup`, `NM_001319174.2:c.650_653dup`, `NM_006894.6:c.839_842dup`

## 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 2.257, GERP 0.974, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.314, pLI 4.5714e-12. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 9**, 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}

**FMO3** population constraint: LOEUF 1.314, pLI 4.5714e-12, missense-Z 0.20944. *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):

- **trimethylaminuria** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 95.50, 92% of residues very-high.

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

*Describes the biological roles of FMO3 (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:** FMO3's established molecular role includes hypotaurine monooxygenase activity. In Reactome, FMO3 is annotated in disease pathway(s) including **Defective FMO3 causes TMAU**.

**Disease mechanism (Reactome):** FMO3 loss or alteration is curated in [Defective FMO3 causes TMAU](https://reactome.org/content/detail/R-HSA-5579019).

### Pathways affected {#pathways}

FMO3 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective FMO3 causes TMAU](https://reactome.org/content/detail/R-HSA-5579019) | curated |
| [FMO oxidises nucleophiles](https://reactome.org/content/detail/R-HSA-217271) | curated |

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

**Molecular function:** hypotaurine monooxygenase activity.

**Biological process:** taurine biosynthetic process.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-05-10.

**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 | 2023-05-10 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related FMO3 variant pages (same residue, condition, or type): [FMO3 p.Ser374fs](/variant/fmo3-p-ser374fs), [FMO3 p.Asn35fs](/variant/fmo3-p-asn35fs), [FMO3 p.Leu40fs](/variant/fmo3-p-leu40fs), [FMO3 p.Met413fs](/variant/fmo3-p-met413fs), [FMO3 c.1184-32dup](/variant/fmo3-c-1184-minus-32dup).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2863131). 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.*