# NM_022132.5(MCCC2):c.1017G>A (p.Val339=)

https://sugi.bio/variant/mccc2-p-val339

## Summary

**MCCC2 p.Val339= (c.1017G>A)** is classified **Likely benign** in MCCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-12-08). Ultra-rare (popmax 0.0134%, eas).

**At a glance:** Likely benign · review: Single submitter · rsID rs1580325457 · 1 submitter · ultra-rare (popmax 0.0134%, eas)

## For patients & families {#patients}

This is a change in the MCCC2 gene that is classified as likely benign — not considered disease-causing, 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 | [MCCC2](https://sugi.bio/atlas/gene/MCCC2/) |
| Protein change (HGVS p.) | p.Val339= |
| Coding change (HGVS c.) | c.1017G>A |
| MANE Select transcript | [NM_022132](https://www.ncbi.nlm.nih.gov/nuccore/NM_022132) |
| dbSNP | [rs1580325457](https://www.ncbi.nlm.nih.gov/snp/rs1580325457/) |
| Variant type | single nucleotide variant |
| Location | chr5:71641020-71641020 (GRCh38) |
| ClinVar | [VCV734092](https://www.ncbi.nlm.nih.gov/clinvar/variation/734092/) |

**All HGVS expressions:** `NC_000005.10:g.71641020G>A`, `NC_000005.9:g.70936847G>A`, `NG_008882.1:g.58733G>A`, `NM_001363147.1:c.903G>A`, `NM_022132.5:c.1017G>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.38) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 3.78, GERP -0.162, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 4.141**. 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 deltas (raw): acceptor loss **0.38**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 17 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.*
- Population frequency (gnomAD v4.1): grpmax **0.0134%** (eas) · FAF95 0.00579% · FAF99 0.00394% · 6/44,860 in the highest group · 8/1,614,046 alleles overall — ultra-rare (popmax 0.0134%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0134% | 7,477 |
| European (non-Finnish) | 0.00017% | 589,960 |

*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}

**MCCC2** population constraint: LOEUF 0.832, pLI 1.8706e-10, missense-Z 0.45938. *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):

- **3-methylcrotonyl-CoA carboxylase deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **339** lies in the coa carboxyltransferase c-terminal domain; the 'carboxyltransferase' region; a UniProt-annotated variant site (in mcc2d; severe form).

AlphaFold model confidence (whole protein): pLDDT 94.82, 93% of residues very-high.

**14 experimental structure(s)** (PDB): [8J4Z](https://www.rcsb.org/structure/8J4Z), [8J73](https://www.rcsb.org/structure/8J73), [8J78](https://www.rcsb.org/structure/8J78), [8J7D](https://www.rcsb.org/structure/8J7D), [8J99](https://www.rcsb.org/structure/8J99), [8JAK](https://www.rcsb.org/structure/8JAK).

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

*Describes the biological roles of MCCC2 (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:** p.Val339= falls in the coa carboxyltransferase c-terminal domain. In Reactome, MCCC2 is annotated in disease pathway(s) including **3-Methylcrotonyl-CoA carboxylase deficiency**, **Defective HLCS causes multiple carboxylase deficiency**.

**Disease mechanism (Reactome):** MCCC2 loss or alteration is curated in [3-Methylcrotonyl-CoA carboxylase deficiency](https://reactome.org/content/detail/R-HSA-9909438), [Defective HLCS causes multiple carboxylase deficiency](https://reactome.org/content/detail/R-HSA-3371599).

### Pathways affected {#pathways}

MCCC2 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [3-Methylcrotonyl-CoA carboxylase deficiency](https://reactome.org/content/detail/R-HSA-9909438) | other |
| ⚕ [Defective HLCS causes multiple carboxylase deficiency](https://reactome.org/content/detail/R-HSA-3371599) | other |
| [Biotin transport and metabolism](https://reactome.org/content/detail/R-HSA-196780) | other |
| [Branched-chain amino acid catabolism](https://reactome.org/content/detail/R-HSA-70895) | other |

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

**Biological process:** L-leucine catabolic process.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2017-12-08.

**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 | 2017-12-08 |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Same-residue context {#hotspot}

Residue **339** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MCCC2 p.Val339Met](/variant/mccc2-p-val339met). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MCCC2 variant pages (same residue, condition, or type): [MCCC2 p.Val339Met](/variant/mccc2-p-val339met), [MCCC2 c.1000-2A>G](/variant/mccc2-c-1000-minus-2a-g), [MCCC2 c.1072+1G>A](/variant/mccc2-c-1072-plus-1g-a), [MCCC2 c.1149+1G>A](/variant/mccc2-c-1149-plus-1g-a), [MCCC2 c.1149+1G>T](/variant/mccc2-c-1149-plus-1g-t), [MCCC2 c.1216+1G>A](/variant/mccc2-c-1216-plus-1g-a), [MCCC2 c.1216+2T>A](/variant/mccc2-c-1216-plus-2t-a), [MCCC2 c.1216+2T>C](/variant/mccc2-c-1216-plus-2t-c).

### 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 734092). 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.*