MMAA

Chr 4AR

metabolism of cobalamin associated A

Also known as: cblA

NCBI Gene: 166785 ENSG00000151611 UniProt: Q8IVH4 OMIM: 607481

The encoded protein translocates cobalamin into mitochondria for adenosylcobalamin synthesis, which serves as a coenzyme for methylmalonyl-CoA mutase. Mutations cause vitamin B12-responsive methylmalonic aciduria (cblA type) through an autosomal recessive inheritance pattern. The pathogenic mechanism involves dominant-negative effects that disrupt normal cobalamin transport and metabolism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is involved in the translocation of cobalamin into the mitochondrion, where it is used in the final steps of adenosylcobalamin synthesis. Adenosylcobalamin is a coenzyme required for the activity of methylmalonyl-CoA mutase. Defects in this gene are a cause of methylmalonic aciduria. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Methylmalonic aciduria, vitamin B12-responsive, cblA typeMIM #251100

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · methylmalonic aciduria, cblA type · AR · ClinGen 2022

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.29

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — MMAA

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.29LOEUF

pLI 0.000

Z-score 0.49

OE 0.89 (0.62–1.29)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.33Z-score

OE missense 0.94 (0.84–1.05)

209 obs / 222.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.89 (0.62–1.29)

0≤0.351.4

Missense OE?0.94 (0.84–1.05)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 20 / 22.5Missense obs/exp: 209 / 222.9Syn Z: 0.13

Background carrier burden — how many people carry a rare variant somewhere in MMAA?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

494 rare PASS variants

Rare truncating (LoF)

1 in 650

88 rare PASS variants

Rare synonymous (reference)

1 in 190

167 rare PASS variants

Rare missense and truncating variants are carried at similar rates in MMAA; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 130	1 in 590
South Asian	~43k	1 in 140	1 in 950
Remaining (unassigned)	~30k	1 in 100	1 in 550
European (Finnish)	~27k	1 in 720	1 in 1,800
Admixed American	~22k	1 in 160	1 in 1,700
African / African American	~21k	1 in 110	1 in 1,400
East Asian	~20k	1 in 140	1 in 3,300
Ashkenazi Jewish	~13k	1 in 1,200	none seen
Middle Eastern	~2,884	1 in 140	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 6 coding exons well covered in gnomAD exomes and genomes.? see exons ↓