MMADHC

Chr 2AR

metabolism of cobalamin associated D

Also known as: C2orf25, CL25022, HMAD, MACD, MAHCD, cblD

NCBI Gene: 27249ENSG00000168288UniProt: Q9H3L0

This gene encodes a mitochondrial protein that is involved in an early step of vitamin B12 metabolism. Vitamin B12 (cobalamin) is essential for normal development and survival in humans. Mutations in this gene cause methylmalonic aciduria and homocystinuria type cblD (MMADHC), a disorder of cobalamin metabolism that is characterized by decreased levels of the coenzymes adenosylcobalamin and methylcobalamin. Pseudogenes have been identified on chromosomes 11 and X.[provided by RefSeq, Nov 2008]

Primary Disease Associations & Inheritance

Homocystinuria-megaloblastic anemia, cblD typeMIM #620952
AR
Methylmalonic aciduria and homocystinuria, cblD typeMIM #277410
AR
Methylmalonic aciduria, cblD typeMIM #620953
AR
423
ClinVar variants
91
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— MMADHC
🧬
Gene-Disease Validity (ClinGen)
inborn disorder of cobalamin metabolism and transport · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
91 Pathogenic / Likely Pathogenic· 98 VUS of 423 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.99LOEUF
pLI 0.000
Z-score 1.59
OE 0.59 (0.36–0.99)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.41Z-score
OE missense 1.09 (0.96–1.24)
168 obs / 153.6 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.59 (0.36–0.99)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.09 (0.96–1.24)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.04
0≤1.21.6
LoF obs/exp: 10 / 17.1Missense obs/exp: 168 / 153.6Syn Z: -0.25

ClinVar Variant Classifications

423 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic55
Likely Pathogenic36
VUS98
Likely Benign198
Benign23
Conflicting13
55
Pathogenic
36
Likely Pathogenic
98
VUS
198
Likely Benign
23
Benign
13
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
17
1
37
0
55
Likely Pathogenic
22
2
12
0
36
VUS
2
75
18
3
98
Likely Benign
0
6
95
97
198
Benign
0
0
21
2
23
Conflicting
—13
Total4184183102423

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

MMADHC · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

MMADHC-related methylmalonic aciduria and homocystinuria, cblD type

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Homocystinuria-megaloblastic anemia, cblD type

MIM #620952

Molecular basis of disorder known

Autosomal recessive

Methylmalonic aciduria and homocystinuria, cblD type

MIM #277410

Molecular basis of disorder known

Autosomal recessive

Methylmalonic aciduria, cblD type

MIM #620953

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — MMADHC
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
An unusual Co-S bond links B(12) chaperones in an interprotein complex.
Mascarenhas R et al.·Proc Natl Acad Sci U S A
2025
Structural features of recombinant MMADHC isoforms and their interactions with MMACHC, proteins of mammalian vitamin B12 metabolism.
Deme JC et al.·Mol Genet Metab
2012
The common homocystinuria-associated P1173L variant of human methionine synthase impairs reductive methylation.
Guha A et al.·J Biol Chem
2025
Characterization of functional domains of the cblD (MMADHC) gene product.
Jusufi J et al.·J Inherit Metab Dis
2014Functional
Gene identification for the cblD defect of vitamin B12 metabolism.
Coelho D et al.·N Engl J Med
2008
Molecular mechanisms leading to three different phenotypes in the cblD defect of intracellular cobalamin metabolism.
Stucki M et al.·Hum Mol Genet
2012Functional
Report of rapid diagnosis and precise management of MMADHC-related intracellular cobalamin defect.
Bhat V et al.·BMJ Case Rep
2021Case report
Clinical and molecular findings in 37 Turkish patients with isolated methylmalonic acidemia.
Şeker Yılmaz B et al.·Turk J Med Sci
2021Cohort
[Differential diagnosis of a Chinese pedigree with methylmalonic acidemia by next-generation sequencing].
Zhao G et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2022
Molecular picture of cobalamin C/D defects before and after newborn screening era.
Nogueira C et al.·J Med Screen
2017
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools