# NM_000255.4(MMUT):c.385G>C (p.Ala129Pro)

https://sugi.bio/variant/mmut-p-ala129pro

## Summary

**MMUT p.Ala129Pro (c.385G>C)** is classified **Uncertain significance** in MMUT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-29). AlphaMissense: likely pathogenic (0.9925); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the MMUT gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [MMUT](https://sugi.bio/atlas/gene/MMUT/) |
| Protein change (HGVS p.) | p.Ala129Pro |
| Coding change (HGVS c.) | c.385G>C |
| MANE Select transcript | [NM_000255](https://www.ncbi.nlm.nih.gov/nuccore/NM_000255) |
| Variant type | single nucleotide variant |
| Location | chr6:49459082-49459082 (GRCh38) |
| ClinVar | [VCV4526143](https://www.ncbi.nlm.nih.gov/clinvar/variation/4526143/) |

**All HGVS expressions:** `NC_000006.11:g.49426795C>G`, `NC_000006.12:g.49459082C>G`, `NG_007100.1:g.9058G>C`, `NM_000255.4:c.385G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9925)
- REVEL 0.905 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.795 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **donor loss** (Δ 0.79) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.647, GERP 2.09, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 10%** most-pathogenic-predicted substitutions in MMUT (of 4,392 modeled).
- CADD: **PHRED 34.0**. 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 0.94** across the covering region of the MANE Select transcript (49,431,731–49,459,466), spanning 27,735 bp. Chi-square p 0.059. 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 **0.79**, acceptor gain **0.00**, donor gain **0.15**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.15**.
  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**0.75** (loss), gain 0.67 / loss 0.75. 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: **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}

**MMUT** population constraint: LOEUF 1.18, pLI 4.9198e-22, missense-Z 1.0944. *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):

- **methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **129** lies in a UniProt-annotated variant site (in mamm; mut-).

AlphaFold model confidence (whole protein): pLDDT 92.72, 85% of residues very-high.

**6 experimental structure(s)** (PDB): [2XIJ](https://www.rcsb.org/structure/2XIJ), [2XIQ](https://www.rcsb.org/structure/2XIQ), [3BIC](https://www.rcsb.org/structure/3BIC), [8DYJ](https://www.rcsb.org/structure/8DYJ), [8DYL](https://www.rcsb.org/structure/8DYL), [8GJU](https://www.rcsb.org/structure/8GJU).

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

*Describes the biological roles of MMUT (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:** MMUT's established molecular role includes GTPase activity. In Reactome, MMUT is annotated in disease pathway(s) including **Defective MMAA causes MMA, cblA type**, **Defective MUT causes MMAM**.

**Disease mechanism (Reactome):** MMUT loss or alteration is curated in [Defective MMAA causes MMA, cblA type](https://reactome.org/content/detail/R-HSA-3359475), [Defective MUT causes MMAM](https://reactome.org/content/detail/R-HSA-3359478).

### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective MMAA causes MMA, cblA type](https://reactome.org/content/detail/R-HSA-3359475) | curated |
| ⚕ [Defective MUT causes MMAM](https://reactome.org/content/detail/R-HSA-3359478) | curated |
| [Cobalamin (Cbl) metabolism](https://reactome.org/content/detail/R-HSA-9759218) | curated |
| [Propionyl-CoA catabolism](https://reactome.org/content/detail/R-HSA-71032) | curated |

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

**Molecular function:** GTPase activity, methylmalonyl-CoA mutase activity, cobalamin binding, identical protein binding, protein homodimerization activity, modified amino acid binding.

**Biological process:** positive regulation of GTPase activity, homocysteine metabolic process, succinyl-CoA biosynthetic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-29.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-29 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related MMUT variant pages (same residue, condition, or type): [MMUT p.Ala129Val](/variant/mmut-p-ala129val), [MMUT c.1083+2T>A](/variant/mmut-c-1083-plus-2t-a), [MMUT c.1084-10A>G](/variant/mmut-c-1084-minus-10a-g), [MMUT c.1084-2A>G](/variant/mmut-c-1084-minus-2a-g), [MMUT c.1445-2A>G](/variant/mmut-c-1445-minus-2a-g), [MMUT c.1560+1G>T](/variant/mmut-c-1560-plus-1g-t), [MMUT c.1677-1G>A](/variant/mmut-c-1677-minus-1g-a), [MMUT c.1677-1G>C](/variant/mmut-c-1677-minus-1g-c).

### 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 4526143). 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.*