Is MCCC2 p.Ser523= (c.1569C>T) pathogenic?

MCCC2 p.Ser523= (c.1569C>T) is classified Benign/Likely benign in MCCC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-20). Rare (popmax 0.754%, sas); Associated with 3-methylcrotonyl-CoA carboxylase 2 deficiency.

What condition is associated with MCCC2 p.Ser523= (c.1569C>T)?

MCCC2 p.Ser523= (c.1569C>T) is associated with 3-methylcrotonyl-CoA carboxylase 2 deficiency, 3-methylcrotonyl-CoA carboxylase deficiency (ClinVar).

How common is MCCC2 p.Ser523= (c.1569C>T) in the general population?

MCCC2 p.Ser523= (c.1569C>T) is rare (popmax 0.754%, sas) (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.Ser523=

c.1569C>T · rs137961577 · VCV729444

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.754%, sas)

Conditions

3-methylcrotonyl-CoA carboxylase 2 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.33 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.49	GERP -3.4, phastCons 0.13
Overall
CADD	5.975	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.754% South Asian · 687/91,062 alleles

Filtering AF 0.708% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.689%

Overall 0.0486% 784/1,614,020 alleles · rare exomes 752/1,461,716 · genomes 32/152,304 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.754%	133
Remaining individualsnot grpmax-eligible	0.056%	1,786
African / African-American	0.00666%	15,006
Admixed American	0.005%	20,006
European (non-Finnish)	0.00458%	21,851

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.Ser523=
Coding: c.1569C>T
MANE Select: NM_022132
dbSNP: rs137961577
Type: single nucleotide variant
Location: chr5:71652749 (GRCh38)
Gene constraint: LOEUF 0.832 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.82 · 14 PDB
Residue 523: an α-helix; the coa carboxyltransferase c-terminal domain; the 'carboxyltransferase' region; a UniProt-annotated variant site (in mcc2d; has some wild-type residual activity)

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

Also linked: 3-methylcrotonyl-CoA carboxylase deficiency

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

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

Similar variants

MCCC2 p.Ser523Asn Likely pathogenic ★ same residue
MCCC2 p.Ser523Gly Conflicting classifications of pathogenicity ★ ⚠ 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-ser523 (accessed [today's date]).

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