Is MCCC1 p.Ala77= (c.231G>A) pathogenic?

MCCC1 p.Ala77= (c.231G>A) is classified Conflicting classifications of pathogenicity in MCCC1 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-05-01). Ultra-rare (popmax 0.0905%, nfe); Associated with 3-methylcrotonyl-CoA carboxylase 1 deficiency.

What condition is associated with MCCC1 p.Ala77= (c.231G>A)?

MCCC1 p.Ala77= (c.231G>A) is associated with 3-methylcrotonyl-CoA carboxylase 1 deficiency (ClinVar).

How common is MCCC1 p.Ala77= (c.231G>A) in the general population?

MCCC1 p.Ala77= (c.231G>A) is ultra-rare (popmax 0.0905%, nfe) (gnomAD).

How is 3-methylcrotonyl-CoA carboxylase deficiency inherited?

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

MCCC1 p.Ala77=

c.231G>A · rs144230304 · VCV261208

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0905%, nfe)

Conditions

3-methylcrotonyl-CoA carboxylase 1 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.21	GERP -3.1, phastCons 0.41
Overall
CADD	11.01	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0905% European (non-Finnish) · 1,068/1,180,040 alleles

Filtering AF 0.086% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0841%

Overall 0.0752% 1,214/1,614,166 alleles · ultra-rare exomes 1,103/1,461,884 · genomes 111/152,282 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.102%	985
European (non-Finnish)grpmax	0.0905%	1,105
Middle Eastern	0.066%	1,516
Remaining individualsnot grpmax-eligible	0.0544%	1,839
African / African-American	0.024%	4,168
South Asian	0.0187%	5,358
Admixed American	0.01%	10,002
East Asian	0.00446%	22,440

Finnish 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: MCCC1
Protein: p.Ala77=
Coding: c.231G>A
MANE Select: NM_020166
dbSNP: rs144230304
Type: single nucleotide variant
Location: chr3:183092451 (GRCh38)
Gene constraint: LOEUF 0.819 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.53 · 14 PDB
Residue 77: the biotin carboxylation domain; a β-strand

Full MCCC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

3-methylcrotonyl-CoA carboxylase 1 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

MCCC1 p.Ala77Val Uncertain significance ★ ⚠ same residue
MCCC1 c.1268-1G>A Pathogenic ★★ same condition
MCCC1 c.1268-2A>G Pathogenic ★★ same condition
MCCC1 c.137-2A>G Pathogenic/Likely pathogenic ★★ same condition
MCCC1 c.1378-2A>G Pathogenic/Likely pathogenic ★★ same condition
MCCC1 c.1594+1G>A Likely pathogenic ★★ same condition
MCCC1 c.1595-1G>C Likely pathogenic ★★ same condition
MCCC1 c.1681+2T>C 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/mccc1-p-ala77 (accessed [today's date]).

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