Is MCCC2 p.Thr139fs (c.416_423delinsGGACTGTGCCTG) pathogenic?

MCCC2 p.Thr139fs (c.416423delinsGGACTGTGCCTG) is classified Likely pathogenic in MCCC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-23). Associated with 3-methylcrotonyl-CoA carboxylase 2 deficiency.

What condition is associated with MCCC2 p.Thr139fs (c.416_423delinsGGACTGTGCCTG)?

MCCC2 p.Thr139fs (c.416_423delinsGGACTGTGCCTG) is associated with 3-methylcrotonyl-CoA carboxylase 2 deficiency (ClinVar).

How is 3-methylcrotonyl-CoA carboxylase deficiency inherited?

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

MCCC2 p.Thr139fs

c.416_423delinsGGACTGTGCCTG · VCV4816104

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

3-methylcrotonyl-CoA carboxylase 2 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 4.9, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: MCCC2
Protein: p.Thr139fs
Coding: c.416_423delinsGGACTGTGCCTG
MANE Select: NM_022132
Type: Indel
Location: chr5:71602538 (GRCh38)
Gene constraint: LOEUF 0.832 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.82 · 14 PDB
Residue 139: the coa carboxyltransferase n-terminal domain; a UniProt-annotated variant site (in mcc2d); the 'carboxyltransferase' region; a turn

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.Thr139Ile Likely pathogenic ★★ same residue
MCCC2 p.Thr139= Likely benign ★★ same residue
MCCC2 p.Asn395_Leu398delinsSerIleTer Pathogenic/Likely pathogenic ★★ same condition
MCCC2 c.511+2_511+3delinsGG Likely pathogenic ★ same condition
MCCC2 p.Glu253fs Likely pathogenic ★ same condition
MCCC2 p.His282fs Likely pathogenic ★ same condition
MCCC2 p.Ile531Phe Uncertain significance ★ same condition
MCCC2 p.Pro186_Asp187delinsLeuValGluValSerVal Conflicting classifications of pathogenicity ★ 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-thr139fs (accessed [today's date]).

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