Is MCCC2 p.Ile231Phe (c.691A>T) pathogenic?

MCCC2 p.Ile231Phe (c.691A>T) is classified Likely pathogenic in MCCC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-26). AlphaMissense: likely pathogenic (0.6636); Very rare (popmax 0.0011%, sas); Associated with 3-methylcrotonyl-CoA carboxylase 2 deficiency.

What condition is associated with MCCC2 p.Ile231Phe (c.691A>T)?

MCCC2 p.Ile231Phe (c.691A>T) is associated with 3-methylcrotonyl-CoA carboxylase 2 deficiency (ClinVar).

How common is MCCC2 p.Ile231Phe (c.691A>T) in the general population?

MCCC2 p.Ile231Phe (c.691A>T) is very rare (popmax 0.0011%, sas) (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.Ile231Phe (c.691A>T)?

AlphaMissense predicts likely pathogenic (score 0.6636) — an in-silico prediction, not a clinical call.

MCCC2 p.Ile231Phe

c.691A>T · rs531567604 · VCV1521022

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6636 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

3-methylcrotonyl-CoA carboxylase 2 deficiency

Computational evidence

Protein change
AlphaMissense	0.6636	likely pathogenic ✓ concordant with ClinVar
REVEL	0.908	moderately pathogenic-leaning
SaProt	LLR -12.57	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 69 kb · p 0.42 · regional, not allelic
Overall
CADD	23.7	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 0.0011% South Asian · 1/91,086 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00031% 5/1,614,162 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,510
South Asiangrpmax	0.0011%	91,086
European (non-Finnish)	0.000254%	393,343

Remaining individuals 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: MCCC2
Protein: p.Ile231Phe
Coding: c.691A>T
MANE Select: NM_022132
dbSNP: rs531567604
Type: single nucleotide variant
Location: chr5:71626706 (GRCh38)
Gene constraint: LOEUF 0.832 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.82 · 14 PDB
Residue 231: the coa carboxyltransferase n-terminal domain; the 'carboxyltransferase' region; a β-strand

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

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

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

Similar variants

MCCC2 p.Ile231Met Conflicting classifications of pathogenicity ★ ⚠ 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-ile231phe (accessed [today's date]).

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