# NM_001040716.2(PC):c.496G>A (p.Val166Ile)

https://sugi.bio/variant/pc-p-val166ile

## Summary

**PC p.Val166Ile (c.496G>A)** is classified **Conflicting classifications of pathogenicity** in PC (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-08-03). AlphaMissense: likely benign (0.1193); Rare (popmax 0.1%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs147697454 · 6 submitters · 2 linked conditions · AlphaMissense likely benign · rare (popmax 0.1%, nfe)

## For patients & families {#patients}

This is a change in the PC gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 6 submitters, and is linked to Inborn genetic diseases.

*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 | [PC](https://sugi.bio/atlas/gene/PC/) |
| Protein change (HGVS p.) | p.Val166Ile |
| Coding change (HGVS c.) | c.496G>A |
| MANE Select transcript | [NM_001040716](https://www.ncbi.nlm.nih.gov/nuccore/NM_001040716) |
| dbSNP | [rs147697454](https://www.ncbi.nlm.nih.gov/snp/rs147697454/) |
| Variant type | single nucleotide variant |
| Location | chr11:66871189-66871189 (GRCh38) |
| ClinVar | [VCV203919](https://www.ncbi.nlm.nih.gov/clinvar/variation/203919/) |

**All HGVS expressions:** `NC_000011.10:g.66871189C>T`, `NC_000011.9:g.66638660C>T`, `NG_008319.1:g.92188G>A`, `NM_000920.4:c.496G>A`, `NM_001040716.1:c.496G>A`, `NM_001040716.2:c.496G>A`, `NM_022172.3:c.496G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1193)
- REVEL 0.555 (indeterminate)
- SaProt LLR -8.532 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 7.617, GERP 1.99, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.1**. 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.*
- Regional missense constraint: **o/e 0.74** across the covering region of the MANE Select transcript (66,849,101–66,872,159), spanning 23,058 bp. Chi-square p 3.1e-25. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. This allele is not in the release, so all four of its deltas are under 0.2. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, and here that is proven rather than inferred: a different substitution at this very position, C>A, IS in the release and scores Δ0.56 acceptor gain, so SpliceAI evaluated this position and this allele was not among the ones that cleared the filter. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.1%** (nfe) · FAF95 0.0954% · FAF99 0.0936% · 1,182/1,179,278 in the highest group · 1,316/1,613,058 alleles overall — rare (popmax 0.1%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.1% | 998 |
| Admixed American | 0.0934% | 1,071 |
| Remaining individuals (not grpmax-eligible) | 0.0881% | 1,135 |
| African / African-American | 0.028% | 3,573 |
| East Asian | 0.00223% | 44,836 |
| South Asian | 0.0011% | 91,002 |

*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 **166** lies in the biotin carboxylation domain; the atp-grasp 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.Val166Ile falls in the biotin carboxylation 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-08-03.

**Submitter consensus:** conflicting (5 Uncertain significance, 1 Likely benign).

**Submission history:** 6 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-11-08 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-02-26 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-28 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-04-27 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-01 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-08-03 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [pyruvate carboxylase deficiency disease](https://sugi.bio/atlas/disease/pyruvate-carboxylase-deficiency-disease/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, Pyruvate carboxylase deficiency, not specified, AllHighlyPenetrant, none provided, LEIGH NECROTIZING ENCEPHALOPATHY DUE TO PYRUVATE CARBOXYLASE DEFICIENCY, LEIGH SYNDROME DUE TO PYRUVATE CARBOXYLASE DEFICIENCY, PC DEFICIENCY, ATAXIA WITH LACTIC ACIDOSIS II.

## Similar variants {#similar}

Related PC variant pages (same residue, condition, or type): [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), [PC p.Arg18Ter](/variant/pc-p-arg18ter), [PC p.Arg263Ter](/variant/pc-p-arg263ter).

### 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 203919). 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.*