Is MCCC2 p.Arg327Lys (c.980G>A) pathogenic?

MCCC2 p.Arg327Lys (c.980G>A) is classified Uncertain significance in MCCC2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely benign (0.0847); Absent from gnomAD v4.1; Associated with 3-methylcrotonyl-CoA carboxylase 2 deficiency.

What condition is associated with MCCC2 p.Arg327Lys (c.980G>A)?

MCCC2 p.Arg327Lys (c.980G>A) is associated with 3-methylcrotonyl-CoA carboxylase 2 deficiency (ClinVar).

How common is MCCC2 p.Arg327Lys (c.980G>A) in the general population?

MCCC2 p.Arg327Lys (c.980G>A) is absent from gnomAD v4.1 (gnomAD).

How is 3-methylcrotonyl-CoA carboxylase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MCCC2 p.Arg327Lys (c.980G>A)?

AlphaMissense predicts likely benign (score 0.0847) — an in-silico prediction, not a clinical call.

MCCC2 p.Arg327Lys

c.980G>A · VCV4057531

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0847 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

3-methylcrotonyl-CoA carboxylase 2 deficiency

Computational evidence

Protein change
AlphaMissense	0.0847	likely benign
REVEL	0.514	indeterminate
SaProt	LLR -7.32	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 69 kb · p 0.42 · regional, not allelic
Overall
CADD	17.68	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MCCC2
Protein: p.Arg327Lys
Coding: c.980G>A
MANE Select: NM_022132
Type: single nucleotide variant
Location: chr5:71635227 (GRCh38)
Gene constraint: LOEUF 0.832 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.82 · 14 PDB
Residue 327: a β-strand; the coa carboxyltransferase c-terminal domain; the 'carboxyltransferase' region

Full MCCC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

3-methylcrotonyl-CoA carboxylase 2 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For 3-methylcrotonyl-CoA carboxylase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

MCCC2 p.Arg327= Uncertain significance same residue
MCCC2 p.Arg327Gly Uncertain significance ⚠ same residue
MCCC2 c.1000-2A>G Likely pathogenic ★★ same condition
MCCC2 c.1072+1G>A Likely pathogenic ★★ same condition
MCCC2 c.1149+1G>A Pathogenic/Likely pathogenic ★★ same condition
MCCC2 c.1149+1G>T Pathogenic/Likely pathogenic ★★ same condition
MCCC2 c.1216+1G>A Likely pathogenic ★★ same condition
MCCC2 c.1216+2T>A Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mccc2-p-arg327lys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown