# NM_016098.4(MPC1):c.289C>T (p.Arg97Trp)

https://sugi.bio/variant/mpc1-p-arg97trp

## Summary

**MPC1 p.Arg97Trp (c.289C>T)** is classified **Pathogenic** in MPC1 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-06-14). AlphaMissense: likely pathogenic (0.9388); Very rare (popmax 0.000509%, nfe); Associated with mitochondrial pyruvate carrier deficiency.

**At a glance:** Pathogenic · review: Single submitter · rsID rs387907237 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.000509%, nfe)

## For patients & families {#patients}

This is a change in the MPC1 gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to mitochondrial pyruvate carrier 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) | Autosomal recessive |
| Age of onset (of this condition) | Neonatal |
| Diagnostic panels | MPC1 is a diagnostic-grade gene on 7 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017771/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MPC1](https://sugi.bio/atlas/gene/MPC1/) |
| Protein change (HGVS p.) | p.Arg97Trp |
| Coding change (HGVS c.) | c.289C>T |
| MANE Select transcript | [NM_016098](https://www.ncbi.nlm.nih.gov/nuccore/NM_016098) |
| dbSNP | [rs387907237](https://www.ncbi.nlm.nih.gov/snp/rs387907237/) |
| Variant type | single nucleotide variant |
| Location | chr6:166365990-166365990 (GRCh38) |
| ClinVar | [VCV35561](https://www.ncbi.nlm.nih.gov/clinvar/variation/35561/) |

**All HGVS expressions:** `NC_000006.11:g.166779478G>A`, `NC_000006.12:g.166365990G>A`, `NG_032888.1:g.22024C>T`, `NM_001270879.2:c.160C>T`, `NM_016098.4:c.289C>T`, `NR_073093.2:n.582C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9388) — concordant with the pathogenic call
- REVEL 0.856 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.947 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **donor loss** (Δ 0.25) — consistent with the pathogenic call
- Conservation: phyloP 6.367, GERP -0.831, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 31.0**. 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 0.80** across the covering region of the MANE Select transcript (166,365,432–166,366,842), spanning 1,410 bp. Chi-square p 0.063. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.25**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 16 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.33** (loss), gain 0.01 / loss 0.33. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000509%** (nfe) · FAF95 0.000183% · FAF99 0.00012% · 6/1,179,186 in the highest group · 7/1,612,856 alleles overall — very rare (popmax 0.000509%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00156% | 63,972 |
| European (non-Finnish) (grpmax) | 0.000509% | 196,531 |

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}

**MPC1** population constraint: LOEUF 0.919, pLI 0.10115, missense-Z 0.8216. *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):

- **mitochondrial disease** — Definitive (AR)

## Protein context {#protein}

Residue **97** lies in a UniProt-annotated variant site (in mpycd; inactive); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 92.85, 85% of residues very-high.

**13 experimental structure(s)** (PDB): [8YW6](https://www.rcsb.org/structure/8YW6), [8YW8](https://www.rcsb.org/structure/8YW8), [8YW9](https://www.rcsb.org/structure/8YW9), [9KNW](https://www.rcsb.org/structure/9KNW), [9KNX](https://www.rcsb.org/structure/9KNX), [9KNY](https://www.rcsb.org/structure/9KNY).

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

*Describes the biological roles of MPC1 (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.*


### Pathways affected {#pathways}

MPC1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Pyruvate metabolism](https://reactome.org/content/detail/R-HSA-70268) | electronic |

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

**Biological process:** pyruvate import into mitochondria.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-06-14.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2012–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2012-07-06 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2024-06-14 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Mitochondrial pyruvate carrier deficiency.

## Same-residue context {#hotspot}

Residue **97** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MPC1 p.Arg97Gln](/variant/mpc1-p-arg97gln). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MPC1 variant pages (same residue, condition, or type): [MPC1 p.Arg97Gln](/variant/mpc1-p-arg97gln), [MPC1 p.Ala70Thr](/variant/mpc1-p-ala70thr), [MPC1 p.Lys72Glu](/variant/mpc1-p-lys72glu), [MPC1 p.Pro37Ser](/variant/mpc1-p-pro37ser), [MPC1 p.Gln74Lys](/variant/mpc1-p-gln74lys), [MPC1 p.Leu92Val](/variant/mpc1-p-leu92val), [MPC1 p.Leu79His](/variant/mpc1-p-leu79his), [MPC1 p.Arg76Gln](/variant/mpc1-p-arg76gln).

### 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 35561). 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.*