Is MCCC2 p.Ile437Val (c.1309A>G) pathogenic?

MCCC2 p.Ile437Val (c.1309A>G) is classified Pathogenic/Likely pathogenic in MCCC2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-10-01). AlphaMissense: likely benign (0.0909); Very rare (popmax 0.00568%, nfe); Associated with 3-methylcrotonyl-CoA carboxylase deficiency.

What condition is associated with MCCC2 p.Ile437Val (c.1309A>G)?

MCCC2 p.Ile437Val (c.1309A>G) is associated with 3-methylcrotonyl-CoA carboxylase deficiency, 3-methylcrotonyl-CoA carboxylase 2 deficiency (ClinVar).

How common is MCCC2 p.Ile437Val (c.1309A>G) in the general population?

MCCC2 p.Ile437Val (c.1309A>G) is very rare (popmax 0.00568%, 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.Ile437Val (c.1309A>G)?

AlphaMissense predicts likely benign (score 0.0909) — an in-silico prediction, not a clinical call.

MCCC2 p.Ile437Val

c.1309A>G · rs119103224 · VCV1925

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0909 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00568%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

3-methylcrotonyl-CoA carboxylase deficiency

Computational evidence

Protein change
AlphaMissense	0.0909	likely benign ⚠ discordant with ClinVar
REVEL	0.745	pathogenic-leaning
SaProt	LLR -7.00	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	Δ0.69	donor gain · deltas
Pangolin	Δ0.48	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 69 kb · p 0.42 · regional, not allelic
Overall
CADD	25.9	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 0.00568% European (non-Finnish) · 67/1,180,028 alleles

Filtering AF 0.00453% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00417%

Overall 0.00421% 68/1,614,094 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00568%	17,612
African / African-American	0.00133%	74,926

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.Ile437Val
Coding: c.1309A>G
MANE Select: NM_022132
dbSNP: rs119103224
Type: single nucleotide variant
Location: chr5:71649189 (GRCh38)
Gene constraint: LOEUF 0.832 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.82 · 14 PDB
Residue 437: a β-strand; the coa carboxyltransferase c-terminal domain; the 'carboxyltransferase' region; a UniProt-annotated variant site (in mcc2d; mild form)

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 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
MCCC2 c.129+1G>T 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-ile437val (accessed [today's date]).

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