Is MCCC2 p.Val526= (c.1578A>G) pathogenic?

MCCC2 p.Val526= (c.1578A>G) is classified Benign in MCCC2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-28). Low-frequency (popmax 3.39%, afr); Associated with 3-methylcrotonyl-CoA carboxylase 2 deficiency.

What condition is associated with MCCC2 p.Val526= (c.1578A>G)?

MCCC2 p.Val526= (c.1578A>G) is associated with 3-methylcrotonyl-CoA carboxylase 2 deficiency, 3-methylcrotonyl-CoA carboxylase deficiency (ClinVar).

How common is MCCC2 p.Val526= (c.1578A>G) in the general population?

MCCC2 p.Val526= (c.1578A>G) is low-frequency (popmax 3.39%, afr) (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.Val526=

c.1578A>G · rs114527907 · VCV261558

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.39%, afr)

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.73	GERP -0.54, phastCons 1
Overall
CADD	7.11	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.39% African / African-American · 2,544/74,952 alleles

Filtering AF 3.28% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.24%

Overall 0.175% 2,814/1,612,588 alleles · low-frequency exomes 1,333/1,460,362 · genomes 1,481/152,226 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.39%	29
Remaining individualsnot grpmax-eligible	0.173%	578
Admixed American	0.168%	594
Middle Eastern	0.099%	1,010
European (non-Finnish)	0.00441%	22,667
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,590
South Asian	0.0022%	45,526

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.Val526=
Coding: c.1578A>G
MANE Select: NM_022132
dbSNP: rs114527907
Type: single nucleotide variant
Location: chr5:71656746 (GRCh38)
Gene constraint: LOEUF 0.832 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.82 · 14 PDB
Residue 526: 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

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.Val526Leu 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
MCCC2 c.1216+2T>A Pathogenic/Likely pathogenic ★★ same condition
MCCC2 c.1216+2T>C 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-val526 (accessed [today's date]).

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