# NM_001040716.2(PC):c.2193G>C (p.Val731=)

https://sugi.bio/variant/pc-p-val731

## Summary

**PC p.Val731= (c.2193G>C)** is classified **Likely benign** in PC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-10). Very rare (popmax 0.000339%, nfe); Associated with pyruvate carboxylase deficiency disease.

**At a glance:** Likely benign · review: Single submitter · rsID rs779640009 · 1 submitter · 1 linked condition · very rare (popmax 0.000339%, nfe)

## For patients & families {#patients}

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

*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, Not applicable |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PC is a diagnostic-grade gene on 13 Genomics England panels |

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

- Increased circulating lactate concentration — Very frequent (99-80%)
- Lactic acidosis — Very frequent (99-80%)
- Elevated lactate:pyruvate ratio — Very frequent (99-80%)
- Seizure — Frequent (79-30%)
- Failure to thrive — Frequent (79-30%)
- Growth delay — Frequent (79-30%)
- Metabolic acidosis — Frequent (79-30%)
- Hyperammonemia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007512/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PC](https://sugi.bio/atlas/gene/PC/) |
| Protein change (HGVS p.) | p.Val731= |
| Coding change (HGVS c.) | c.2193G>C |
| MANE Select transcript | [NM_001040716](https://www.ncbi.nlm.nih.gov/nuccore/NM_001040716) |
| dbSNP | [rs779640009](https://www.ncbi.nlm.nih.gov/snp/rs779640009/) |
| Variant type | single nucleotide variant |
| Location | chr11:66851070-66851070 (GRCh38) |
| ClinVar | [VCV2841099](https://www.ncbi.nlm.nih.gov/clinvar/variation/2841099/) |

**All HGVS expressions:** `NC_000011.10:g.66851070C>G`, `NC_000011.9:g.66618541C>G`, `NG_008319.1:g.112307G>C`, `NG_123025.1:g.347C>G`, `NM_000920.4:c.2193G>C`, `NM_001040716.2:c.2193G>C`, `NM_022172.3:c.2193G>C`

## 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 1.071, GERP 0.221, phastCons 1 — weakly conserved position
- CADD: **PHRED 8.245**. 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, Δ0.79 donor 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 (gnomAD v4.1): grpmax **0.000339%** (nfe) · FAF95 7.9e-05% · FAF99 5.4e-05% · 4/1,180,008 in the highest group · 8/1,613,194 alleles overall — very rare (popmax 0.000339%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00634% | 15,763 |
| European (non-Finnish) (grpmax) | 0.000339% | 295,002 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**PC** population constraint: LOEUF 0.539, pLI 0.065118, missense-Z 3.7757; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *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 **731** lies in an α-helix; the pyruvate carboxyltransferase domain.

AlphaFold model confidence (whole protein): pLDDT 90.53, 71% of residues very-high.

**10 experimental structure(s)** (PDB): [3BG3](https://www.rcsb.org/structure/3BG3), [3BG9](https://www.rcsb.org/structure/3BG9), [7WTA](https://www.rcsb.org/structure/7WTA), [7WTB](https://www.rcsb.org/structure/7WTB), [7WTC](https://www.rcsb.org/structure/7WTC), [7WTD](https://www.rcsb.org/structure/7WTD) — incl. mutant structure 3BG9.

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

*Describes the biological roles of PC (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:** PC's established molecular role includes pyruvate carboxylase activity. p.Val731= falls in the pyruvate carboxyltransferase domain. In Reactome, PC is annotated in disease pathway(s) including **Defective HLCS causes multiple carboxylase deficiency**.

**Disease mechanism (Reactome):** PC loss or alteration is curated in [Defective HLCS causes multiple carboxylase deficiency](https://reactome.org/content/detail/R-HSA-3371599).

### Pathways affected {#pathways}

PC participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective HLCS causes multiple carboxylase deficiency](https://reactome.org/content/detail/R-HSA-3371599) | curated |
| [Biotin transport and metabolism](https://reactome.org/content/detail/R-HSA-196780) | curated |
| [Gluconeogenesis](https://reactome.org/content/detail/R-HSA-70263) | curated |
| [Pyruvate metabolism](https://reactome.org/content/detail/R-HSA-70268) | curated |

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

**Molecular function:** pyruvate carboxylase activity, identical protein binding.

**Biological process:** NADP+ metabolic process, negative regulation of gene expression, viral RNA genome packaging, viral release from host cell, NAD+ metabolic process, host-mediated activation of viral process.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-10.

**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 | 2025-11-10 |

## Associated conditions {#conditions}

[pyruvate carboxylase deficiency disease](https://sugi.bio/atlas/disease/pyruvate-carboxylase-deficiency-disease/).

**Reported phenotype names (ClinVar):** Pyruvate carboxylase deficiency, Pyruvate Carboxylase Deficiency Disease, ATAXIA WITH LACTIC ACIDOSIS II, LEIGH NECROTIZING ENCEPHALOPATHY DUE TO PYRUVATE CARBOXYLASE DEFICIENCY, LEIGH SYNDROME DUE TO PYRUVATE CARBOXYLASE DEFICIENCY, PC DEFICIENCY.

## Similar variants {#similar}

Related PC variant pages (same residue, condition, or type): [PC p.Val731Ala](/variant/pc-p-val731ala), [PC p.Val731Met](/variant/pc-p-val731met), [PC c.1368+1G>A](/variant/pc-c-1368-plus-1g-a), [PC c.1826-1G>C](/variant/pc-c-1826-minus-1g-c), [PC c.1983-116C>T](/variant/pc-c-1983-minus-116c-t), [PC c.633+2T>C](/variant/pc-c-633-plus-2t-c), [PC p.Ala610Thr](/variant/pc-p-ala610thr), [PC p.Ala812Asp](/variant/pc-p-ala812asp).

### 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 2841099). 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.*