Is MCCC2 p.Ser471fs (c.1412_1413del) pathogenic?

MCCC2 p.Ser471fs (c.14121413del) is classified Pathogenic/Likely pathogenic in MCCC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-28). Very rare (popmax 0.00119%, nfe); Associated with 3-methylcrotonyl-CoA carboxylase 2 deficiency.

What condition is associated with MCCC2 p.Ser471fs (c.1412_1413del)?

MCCC2 p.Ser471fs (c.1412_1413del) is associated with 3-methylcrotonyl-CoA carboxylase 2 deficiency (ClinVar).

How common is MCCC2 p.Ser471fs (c.1412_1413del) in the general population?

MCCC2 p.Ser471fs (c.1412_1413del) is very rare (popmax 0.00119%, nfe) (gnomAD).

How is 3-methylcrotonyl-CoA carboxylase deficiency inherited?

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

MCCC2 p.Ser471fs

c.1412_1413del · rs780304038 · VCV595072

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

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 15 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.2	GERP 1.9, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00119% European (non-Finnish) · 14/1,180,028 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000929% 15/1,614,042 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)grpmax	0.00119%	84,288

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MCCC2
Protein: p.Ser471fs
Coding: c.1412_1413del
MANE Select: NM_022132
dbSNP: rs780304038
Type: Deletion
Location: chr5:71650107 (GRCh38)
Gene constraint: LOEUF 0.832 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.82 · 14 PDB
Residue 471: 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 c.1151del Likely pathogenic ★★ same condition
MCCC2 c.281+1del Likely pathogenic ★★ same condition
MCCC2 c.383+2del Likely pathogenic ★★ same condition
MCCC2 c.739del Pathogenic/Likely pathogenic ★★ same condition
MCCC2 p.Asn230fs Pathogenic/Likely pathogenic ★★ same condition
MCCC2 p.Gly118del Pathogenic/Likely pathogenic ★★ same condition
MCCC2 p.Gly368fs Pathogenic/Likely pathogenic ★★ same condition
MCCC2 p.Gly79fs 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-ser471fs (accessed [today's date]).

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