# NM_000531.6(OTC):c.915C>G (p.Pro305=)

https://sugi.bio/variant/otc-p-pro305

## Summary

**OTC p.Pro305= (c.915C>G)** is classified **Likely benign** in OTC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-31). Absent from gnomAD v4.1; Associated with ornithine carbamoyltransferase deficiency.

**At a glance:** Likely benign · review: Single submitter · rsID rs368485863 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the OTC gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to ornithine carbamoyltransferase deficiency.

*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) | X-linked recessive |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 27 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | OTC is a diagnostic-grade gene on 9 Genomics England panels |

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

- Hepatic failure — Very frequent (99-80%)
- Splenomegaly — Very frequent (99-80%)
- Hypoglycemia — Very frequent (99-80%)
- Hyperammonemia — Very frequent (99-80%)
- Aminoaciduria — Very frequent (99-80%)
- Seizure — Frequent (79-30%)
- Hypotonia — Frequent (79-30%)
- Lethargy — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0008391/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [OTC](https://sugi.bio/atlas/gene/OTC/) |
| Protein change (HGVS p.) | p.Pro305= |
| Coding change (HGVS c.) | c.915C>G |
| MANE Select transcript | [NM_000531](https://www.ncbi.nlm.nih.gov/nuccore/NM_000531) |
| dbSNP | [rs368485863](https://www.ncbi.nlm.nih.gov/snp/rs368485863/) |
| Variant type | single nucleotide variant |
| Location | chrX:38411909-38411909 (GRCh38) |
| ClinVar | [VCV1998172](https://www.ncbi.nlm.nih.gov/clinvar/variation/1998172/) |

**All HGVS expressions:** `LRG_846:g.64427C>G`, `LRG_846t1:c.915C>G`, `NC_000023.10:g.38271162C>G`, `NC_000023.11:g.38411909C>G`, `NG_008471.1:g.64427C>G`, `NM_000531.6:c.915C>G`, `NM_001407092.1:c.915C>G`

## 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 0.806, GERP -0.752, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 8.299**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.23 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**OTC** population constraint: ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **ornithine carbamoyltransferase deficiency** — Definitive (XL)

## Protein context {#protein}

Residue **305** lies in a UniProt-annotated variant site (in otcd).

AlphaFold model confidence (whole protein): pLDDT 91.94, 87% of residues very-high.

**4 experimental structure(s)** (PDB): [1C9Y](https://www.rcsb.org/structure/1C9Y), [1EP9](https://www.rcsb.org/structure/1EP9), [1FVO](https://www.rcsb.org/structure/1FVO), [1OTH](https://www.rcsb.org/structure/1OTH).

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

*Describes the biological roles of OTC (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:** OTC's established molecular role includes ornithine carbamoyltransferase activity. In Reactome, OTC is annotated in disease pathway(s) including **OTC leader sequence variants cause OTC deficiency**, **OTC main chain variants cause OTC deficiency**.

**Disease mechanism (Reactome):** OTC loss or alteration is curated in [OTC leader sequence variants cause OTC deficiency](https://reactome.org/content/detail/R-HSA-9956551), [OTC main chain variants cause OTC deficiency](https://reactome.org/content/detail/R-HSA-9956553).

### Pathways affected {#pathways}

OTC participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [OTC leader sequence variants cause OTC deficiency](https://reactome.org/content/detail/R-HSA-9956551) | curated |
| ⚕ [OTC main chain variants cause OTC deficiency](https://reactome.org/content/detail/R-HSA-9956553) | curated |
| [Negative transcriptional regulation of urea cycle enzymes](https://reactome.org/content/detail/R-HSA-9988426) | curated |
| [Urea cycle](https://reactome.org/content/detail/R-HSA-70635) | curated |
| [Mitochondrial protein import](https://reactome.org/content/detail/R-HSA-1268020) | electronic |

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

**Molecular function:** ornithine carbamoyltransferase activity.

**Biological process:** urea cycle, L-ornithine catabolic process, L-citrulline biosynthetic process, ammonium homeostasis.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-05-31.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-05-31 |

## Associated conditions {#conditions}

[ornithine carbamoyltransferase deficiency](https://sugi.bio/atlas/disease/ornithine-carbamoyltransferase-deficiency/).

**Reported phenotype names (ClinVar):** Ornithine carbamoyltransferase deficiency, Ornithine Carbamoyltransferase Deficiency Disease, ORNITHINE TRANSCARBAMYLASE DEFICIENCY, ORNITHINE TRANSCARBAMYLASE DEFICIENCY, HYPERAMMONEMIA DUE TO, OTC DEFICIENCY.

## Same-residue context {#hotspot}

Residue **305** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [OTC p.Pro305His](/variant/otc-p-pro305his), [OTC p.Pro305Arg](/variant/otc-p-pro305arg). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related OTC variant pages (same residue, condition, or type): [OTC p.Pro305Arg](/variant/otc-p-pro305arg), [OTC p.Pro305His](/variant/otc-p-pro305his), [OTC c.298+2T>G](/variant/otc-c-298-plus-2t-g), [OTC c.299-1G>A](/variant/otc-c-299-minus-1g-a), [OTC c.386+1G>A](/variant/otc-c-386-plus-1g-a), [OTC c.540+1G>A](/variant/otc-c-540-plus-1g-a), [OTC c.540+1G>T](/variant/otc-c-540-plus-1g-t), [OTC c.540+265G>A](/variant/otc-c-540-plus-265g-a).

### 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 1998172). 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.*