Is MCCC1 p.Pro152Ser (c.454C>T) pathogenic?

MCCC1 p.Pro152Ser (c.454C>T) is classified Uncertain significance in MCCC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-24). AlphaMissense: ambiguous (0.5401); Very rare (popmax 0.00017%, nfe); Associated with 3-methylcrotonyl-CoA carboxylase 1 deficiency.

What condition is associated with MCCC1 p.Pro152Ser (c.454C>T)?

MCCC1 p.Pro152Ser (c.454C>T) is associated with 3-methylcrotonyl-CoA carboxylase 1 deficiency (ClinVar).

How common is MCCC1 p.Pro152Ser (c.454C>T) in the general population?

MCCC1 p.Pro152Ser (c.454C>T) is very rare (popmax 0.00017%, nfe) (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 MCCC1 p.Pro152Ser (c.454C>T)?

AlphaMissense predicts ambiguous (score 0.5401) — an in-silico prediction, not a clinical call.

MCCC1 p.Pro152Ser

c.454C>T · rs1022408190 · VCV1363783

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5401 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

3-methylcrotonyl-CoA carboxylase 1 deficiency

Computational evidence

Protein change
AlphaMissense	0.5401	ambiguous
REVEL	0.931	moderately pathogenic-leaning
SaProt	LLR -14.09	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 84 kb · p 0.0012 · regional, not allelic
Overall
CADD	28.2	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 0.00017% European (non-Finnish) · 2/1,179,774 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,702 alleles · very rare exomes 2/1,461,568 · genomes 0/152,134 · joint denominator

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.Pro152Ser
Coding: c.454C>T
MANE Select: NM_020166
dbSNP: rs1022408190
Type: single nucleotide variant
Location: chr3:183072403 (GRCh38)
Gene constraint: LOEUF 0.819 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.53 · 14 PDB
Residue 152: 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.Pro152Leu 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
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-pro152ser (accessed [today's date]).

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