Is MCCC2 p.Ala547Val (c.1640C>T) pathogenic?

MCCC2 p.Ala547Val (c.1640C>T) is classified Uncertain significance in MCCC2 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-11-27). AlphaMissense: likely benign (0.1452); Ultra-rare (popmax 0.0165%, mid); Associated with 3-methylcrotonyl-CoA carboxylase 2 deficiency.

What condition is associated with MCCC2 p.Ala547Val (c.1640C>T)?

MCCC2 p.Ala547Val (c.1640C>T) is associated with 3-methylcrotonyl-CoA carboxylase 2 deficiency (ClinVar).

How common is MCCC2 p.Ala547Val (c.1640C>T) in the general population?

MCCC2 p.Ala547Val (c.1640C>T) is ultra-rare (popmax 0.0165%, mid) (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.Ala547Val (c.1640C>T)?

AlphaMissense predicts likely benign (score 0.1452) — an in-silico prediction, not a clinical call.

MCCC2 p.Ala547Val

c.1640C>T · rs778172446 · VCV535827

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1452 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

3-methylcrotonyl-CoA carboxylase 2 deficiency

Computational evidence

Protein change
AlphaMissense	0.1452	likely benign
REVEL	0.757	pathogenic-leaning
SaProt	LLR -13.70	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.66, phastCons 0.98
Regional constraint	o/e 0.97	unconstrained · MANE · 69 kb · p 0.42 · regional, not allelic
Overall
CADD	21.0	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.000479% 7/1,461,822 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
South Asian	0.00659%	15,181

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.Ala547Val
Coding: c.1640C>T
MANE Select: NM_022132
dbSNP: rs778172446
Type: single nucleotide variant
Location: chr5:71656808 (GRCh38)
Gene constraint: LOEUF 0.832 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.82 · 14 PDB
Residue 547: an α-helix; the coa carboxyltransferase c-terminal domain; the 'carboxyltransferase' region

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.Ala547Thr Uncertain significance ★★ ⚠ 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-ala547val (accessed [today's date]).

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