Is MCCC2 p.Arg193Cys (c.577C>T) pathogenic?

MCCC2 p.Arg193Cys (c.577C>T) is classified Pathogenic/Likely pathogenic in MCCC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-01). AlphaMissense: ambiguous (0.3527); Ultra-rare (popmax 0.0103%, nfe); Associated with 3-methylcrotonyl-CoA carboxylase deficiency.

What condition is associated with MCCC2 p.Arg193Cys (c.577C>T)?

MCCC2 p.Arg193Cys (c.577C>T) is associated with 3-methylcrotonyl-CoA carboxylase deficiency, 3-methylcrotonyl-CoA carboxylase 2 deficiency (ClinVar).

How common is MCCC2 p.Arg193Cys (c.577C>T) in the general population?

MCCC2 p.Arg193Cys (c.577C>T) is ultra-rare (popmax 0.0103%, 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 MCCC2 p.Arg193Cys (c.577C>T)?

AlphaMissense predicts ambiguous (score 0.3527) — an in-silico prediction, not a clinical call.

MCCC2 p.Arg193Cys

c.577C>T · rs547662164 · VCV203804

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3527 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

3-methylcrotonyl-CoA carboxylase deficiency

Computational evidence

Protein change
AlphaMissense	0.3527	ambiguous
REVEL	0.91	moderately pathogenic-leaning
SaProt	LLR -14.61	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 4.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 69 kb · p 0.42 · regional, not allelic
Overall
CADD	32.0	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 0.0103% European (non-Finnish) · 121/1,180,000 alleles

Filtering AF 0.00876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0082%

Overall 0.00781% 126/1,613,876 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0103%	9,752
African / African-American	0.00267%	37,423
East Asian	0.00223%	44,882
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,070

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.Arg193Cys
Coding: c.577C>T
MANE Select: NM_022132
dbSNP: rs547662164
Type: single nucleotide variant
Location: chr5:71604421 (GRCh38)
Gene constraint: LOEUF 0.832 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.82 · 14 PDB
Residue 193: the coa carboxyltransferase n-terminal domain; a UniProt-annotated variant site (in mcc2d; mild form); a UniProt-annotated variant site (in mcc2d); the 'carboxyltransferase' region; an α-helix

Full MCCC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

3-methylcrotonyl-CoA carboxylase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: 3-methylcrotonyl-CoA carboxylase 2 deficiency

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

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

Similar variants

MCCC2 p.Arg193His Likely pathogenic ★★ ⚠ 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-arg193cys (accessed [today's date]).

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