MMADHC

Chr 2AR

metabolism of cobalamin associated D

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

NCBI Gene: 27249 ENSG00000168288 UniProt: Q9H3L0 OMIM: 611935

This gene encodes a mitochondrial protein that regulates cobalamin (vitamin B12) metabolism and trafficking, specifically controlling the biosynthesis and proportion of two essential coenzymes, methylcobalamin and adenosylcobalamin. Mutations cause methylmalonic aciduria and homocystinuria cblD type, an autosomal recessive disorder of cobalamin metabolism that can present with megaloblastic anemia and affects both amino acid and organic acid metabolism. The gene shows low constraint against loss-of-function variants (pLI 0.00002, LOEUF 0.994), which is consistent with its autosomal recessive inheritance pattern.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.993 OMIM phenotypes

Clinical Summary— MMADHC

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Gene-Disease Validity (ClinGen)

inborn disorder of cobalamin metabolism and transport · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

77 unique Pathogenic / Likely Pathogenic· 98 VUS of 421 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MMADHC

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.99LOEUF

pLI 0.000

Z-score 1.59

OE 0.59 (0.36–0.99)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.41Z-score

OE missense 1.09 (0.96–1.24)

168 obs / 153.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.59 (0.36–0.99)

0≤0.351.4

Missense OE?1.09 (0.96–1.24)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 10 / 17.1Missense obs/exp: 168 / 153.6Syn Z: -0.25

ClinVar Variant Classifications

421 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic37

Likely Pathogenic40

VUS98

Likely Benign197

Benign23

Conflicting13

Pathogenic

Likely Pathogenic

VUS

197

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	27	2	8	0	37
Likely Pathogenic	38	2	0	0	40
VUS	3	79	13	3	98
Likely Benign	0	6	94	97	197
Benign	0	0	21	2	23
Conflicting	—				13
Total	68	89	136	102	408

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 24) ClinVar copy-number / structural variants overlap MMADHC — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →