Is MCCC1 p.Ala291= (c.873G>A) pathogenic?

MCCC1 p.Ala291= (c.873G>A) is classified Uncertain significance in MCCC1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-09-03). Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with MCCC1 p.Ala291= (c.873G>A)?

MCCC1 p.Ala291= (c.873G>A) is associated with Inborn genetic diseases, 3-methylcrotonyl-CoA carboxylase 1 deficiency, 3-methylcrotonyl-CoA carboxylase deficiency (ClinVar).

How common is MCCC1 p.Ala291= (c.873G>A) in the general population?

MCCC1 p.Ala291= (c.873G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

MCCC1 p.Ala291=

c.873G>A · rs138794621 · VCV167271

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.73	donor gain · deltas
Pangolin	Δ0.78	gain · loss 0.53 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.8	GERP 1.2, phastCons 1
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.00725% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00552%

Overall 0.00282% 45/1,597,604 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
African / African-American	0.0134%	7,466
Remaining individualsnot grpmax-eligible	0.00323%	30,935
European (non-Finnish)	0.00265%	37,731
South Asian	0.00113%	88,710

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.Ala291=
Coding: c.873G>A
MANE Select: NM_020166
dbSNP: rs138794621
Type: single nucleotide variant
Location: chr3:183057311 (GRCh38)
Gene constraint: LOEUF 0.819 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.53 · 14 PDB
Residue 291: the biotin carboxylation domain; the atp-grasp domain; a UniProt-annotated variant site (in mcc1d; associated with a reduction of wild-type residual activity)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: 3-methylcrotonyl-CoA carboxylase 1 deficiency 3-methylcrotonyl-CoA carboxylase deficiency

Similar variants

MCCC1 p.Ala291Glu Uncertain significance ★ ⚠ same residue
MCCC1 p.Ala291Val Conflicting classifications of pathogenicity ★ ⚠ same residue
MCCC1 p.Ala291fs Pathogenic/Likely pathogenic ★★ 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

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-ala291 (accessed [today's date]).

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