Is MCCC2 p.Asn403Ser (c.1208A>G) pathogenic?

MCCC2 p.Asn403Ser (c.1208A>G) is classified Pathogenic/Likely pathogenic in MCCC2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-03-01). AlphaMissense: likely pathogenic (0.6155); Ultra-rare (popmax 0.0255%, nfe); Associated with 3-methylcrotonyl-CoA carboxylase deficiency.

What condition is associated with MCCC2 p.Asn403Ser (c.1208A>G)?

MCCC2 p.Asn403Ser (c.1208A>G) is associated with 3-methylcrotonyl-CoA carboxylase deficiency, 3-methylcrotonyl-CoA carboxylase 2 deficiency (ClinVar).

How common is MCCC2 p.Asn403Ser (c.1208A>G) in the general population?

MCCC2 p.Asn403Ser (c.1208A>G) is ultra-rare (popmax 0.0255%, nfe) (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.Asn403Ser (c.1208A>G)?

AlphaMissense predicts likely pathogenic (score 0.6155) — an in-silico prediction, not a clinical call.

MCCC2 p.Asn403Ser

c.1208A>G · rs142887940 · VCV1483421

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.6155 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0255%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

3-methylcrotonyl-CoA carboxylase deficiency

Computational evidence

Protein change
AlphaMissense	0.6155	likely pathogenic ✓ concordant with ClinVar
REVEL	0.854	moderately pathogenic-leaning
SaProt	LLR -13.06	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 69 kb · p 0.42 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0255% European (non-Finnish) · 301/1,179,738 alleles

Filtering AF 0.0231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.0207% 334/1,613,524 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0449%	2,230
European (non-Finnish)grpmax	0.0255%	3,919
African / African-American	0.00401%	24,957
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
Admixed American	0.00167%	59,990

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.Asn403Ser
Coding: c.1208A>G
MANE Select: NM_022132
dbSNP: rs142887940
Type: single nucleotide variant
Location: chr5:71646269 (GRCh38)
Gene constraint: LOEUF 0.832 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.82 · 14 PDB
Residue 403: the coa carboxyltransferase c-terminal domain; the 'carboxyltransferase' region; a UniProt-annotated variant site (in mcc2d)

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

Disease context

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

Also linked: 3-methylcrotonyl-CoA carboxylase 2 deficiency

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

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

Similar variants

MCCC2 p.Asn403Thr Pathogenic/Likely pathogenic ★★ same residue
MCCC2 p.Asn403fs Likely pathogenic ★ 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-asn403ser (accessed [today's date]).

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