# NM_015506.3(MMACHC):c.*467G>A

https://sugi.bio/variant/mmachc-c-star-467g-a

## Summary

**MMACHC c.*467G>A** is classified **Uncertain significance** in MMACHC (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). Rare (popmax 0.485%, afr); Associated with Disorders of Intracellular Cobalamin Metabolism.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs551671089 · 1 submitter · 1 linked condition · rare (popmax 0.485%, afr)

## For patients & families {#patients}

This is a change in the MMACHC gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Disorders of Intracellular Cobalamin Metabolism.

*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 | [MMACHC](https://sugi.bio/atlas/gene/MMACHC/) |
| Coding change (HGVS c.) | c.*467G>A |
| MANE Select transcript | [NM_015506](https://www.ncbi.nlm.nih.gov/nuccore/NM_015506) |
| dbSNP | [rs551671089](https://www.ncbi.nlm.nih.gov/snp/rs551671089/) |
| Variant type | single nucleotide variant |
| Location | chr1:45509682-45509682 (GRCh38) |
| ClinVar | [VCV875471](https://www.ncbi.nlm.nih.gov/clinvar/variation/875471/) |

**All HGVS expressions:** `NC_000001.10:g.45975354G>A`, `NC_000001.11:g.45509682G>A`, `NG_013378.1:g.14499G>A`, `NM_001330540.2:c.*467G>A`, `NM_015506.3:c.*467G>A`

## 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 -0.313, GERP 0.177 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 2.154**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.485%** (afr) · FAF95 0.43% · FAF99 0.409% · 201/41,432 in the highest group · 207/162,208 alleles overall — rare (popmax 0.485%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.485% | 206 |
| Remaining individuals (not grpmax-eligible) | 0.0778% | 1,285 |
| Admixed American | 0.0243% | 4,115 |

*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}

**MMACHC** population constraint: LOEUF 1.162, pLI 0.00018448, missense-Z -0.13096; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *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 and homocystinuria type cblC** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 86.41, 76% of residues very-high.

**7 experimental structure(s)** (PDB): [3SBY](https://www.rcsb.org/structure/3SBY), [3SBZ](https://www.rcsb.org/structure/3SBZ), [3SC0](https://www.rcsb.org/structure/3SC0), [3SOM](https://www.rcsb.org/structure/3SOM), [5UOS](https://www.rcsb.org/structure/5UOS), [7WUZ](https://www.rcsb.org/structure/7WUZ).

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

*Describes the biological roles of MMACHC (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:** MMACHC's established molecular role includes oxidoreductase activity. In Reactome, MMACHC is annotated in disease pathway(s) including **Defective MMACHC causes MAHCC**, **Defective MMADHC causes MMAHCD**.

**Disease mechanism (Reactome):** MMACHC loss or alteration is curated in [Defective MMACHC causes MAHCC](https://reactome.org/content/detail/R-HSA-3359474), [Defective MMADHC causes MMAHCD](https://reactome.org/content/detail/R-HSA-3359473).

### Pathways affected {#pathways}

MMACHC participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective MMACHC causes MAHCC](https://reactome.org/content/detail/R-HSA-3359474) | curated |
| ⚕ [Defective MMADHC causes MMAHCD](https://reactome.org/content/detail/R-HSA-3359473) | curated |
| [Cobalamin (Cbl) metabolism](https://reactome.org/content/detail/R-HSA-9759218) | curated |

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

**Molecular function:** oxidoreductase activity, transferase activity, transferring alkyl or aryl (other than methyl) groups, demethylase activity, cyanocobalamin reductase (cyanide-eliminating) (NADP+) activity, protein homodimerization activity, glutathione binding.

**Biological process:** glutathione metabolic process, cobalamin metabolic process, demethylation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-01-12.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |

## Associated conditions {#conditions}

[Disorders of Intracellular Cobalamin Metabolism](https://sugi.bio/atlas/disease/disorders-of-intracellular-cobalamin-metabolism/).

**Reported phenotype names (ClinVar):** Disorders of Intracellular Cobalamin Metabolism.

## Similar variants {#similar}

Related MMACHC variant pages (same residue, condition, or type): [MMACHC c.-123A>T](/variant/mmachc-c-minus-123a-t), [MMACHC c.*201G>T](/variant/mmachc-c-star-201g-t), [MMACHC p.Glu106Lys](/variant/mmachc-p-glu106lys), [MMACHC p.Val135Leu](/variant/mmachc-p-val135leu), [MMACHC c.*1144A>T](/variant/mmachc-c-star-1144a-t), [MMACHC c.*1260G>A](/variant/mmachc-c-star-1260g-a), [MMACHC c.*1362G>A](/variant/mmachc-c-star-1362g-a), [MMACHC c.*1585G>C](/variant/mmachc-c-star-1585g-c).

### 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 875471). 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.*