Is MCCC2 p.Asn480Ser (c.1439A>G) pathogenic?

MCCC2 p.Asn480Ser (c.1439A>G) is classified Conflicting classifications of pathogenicity in MCCC2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0573); Rare (popmax 0.85%, afr); Associated with 3-methylcrotonyl-CoA carboxylase 2 deficiency.

What condition is associated with MCCC2 p.Asn480Ser (c.1439A>G)?

MCCC2 p.Asn480Ser (c.1439A>G) is associated with 3-methylcrotonyl-CoA carboxylase 2 deficiency (ClinVar).

How common is MCCC2 p.Asn480Ser (c.1439A>G) in the general population?

MCCC2 p.Asn480Ser (c.1439A>G) is rare (popmax 0.85%, afr) (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.Asn480Ser (c.1439A>G)?

AlphaMissense predicts likely benign (score 0.0573) — an in-silico prediction, not a clinical call.

MCCC2 p.Asn480Ser

c.1439A>G · rs115328026 · VCV507090

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0573 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.85%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

3-methylcrotonyl-CoA carboxylase 2 deficiency

Computational evidence

Protein change
AlphaMissense	0.0573	likely benign
REVEL	0.296	indeterminate
SaProt	LLR -8.09	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 -0.51	GERP -3.7
Regional constraint	o/e 0.97	unconstrained · MANE · 69 kb · p 0.42 · regional, not allelic
Overall
CADD	6.186	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 0.85% African / African-American · 638/75,070 alleles

Filtering AF 0.795% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.773%

Overall 0.0441% 712/1,614,198 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.85%	118
Admixed American	0.0483%	2,070
Remaining individualsnot grpmax-eligible	0.0448%	2,232
Middle Eastern	0.0165%	6,062
South Asian	0.00439%	22,772
European (non-Finnish)	0.00102%	98,334

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.Asn480Ser
Coding: c.1439A>G
MANE Select: NM_022132
dbSNP: rs115328026
Type: single nucleotide variant
Location: chr5:71650134 (GRCh38)
Gene constraint: LOEUF 0.832 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.82 · 14 PDB
Residue 480: an α-helix; 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.Asn480Asp Uncertain significance ★★ ⚠ same residue
MCCC2 p.Asn480= Uncertain significance same residue
MCCC2 p.Asn480Lys 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

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-asn480ser (accessed [today's date]).

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