Methylmalonate semialdehyde dehydrogenase deficiency

Summary

Methylmalonate semialdehyde dehydrogenase deficiency (MONDO:0013579) is a disease caused by ALDH6A1 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Europe)
• Causal gene: ALDH6A1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 97

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	methylmalonate semialdehyde dehydrogenase deficiency
Mondo ID	MONDO:0013579
MeSH	C566402
OMIM	614105
Orphanet	289307
ICD-11	1700759193
UMLS	C3279840
MedGen	481470
GARD	0017322
Is cancer (heuristic)	no

Also known as: developmental delay due to ALDH6A1 deficiency · developmental delay due to methylmalonate semialdehyde dehydrogenase deficiency · developmental delay due to MMSDH deficiency · methylmalonate semialdehyde dehydrogenase deficiency · MMSDHD

Data availability: 97 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn organic aciduria › methylmalonate semialdehyde dehydrogenase deficiency

Related subtypes (6): methylmalonic acidemia, glutaryl-CoA dehydrogenase deficiency, glutaric acidemia type 3, malonic aciduria, maple syrup urine disease, classic organic aciduria

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

97 retrieved; paginated sample, class counts are floors:

48 uncertain significance, 23 benign, 7 likely benign, 7 conflicting classifications of pathogenicity, 6 pathogenic, 5 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
208071	NM_005589.4(ALDH6A1):c.184C>T (p.Pro62Ser)	ALDH6A1	Pathogenic	no assertion criteria provided
208072	NM_005589.4(ALDH6A1):c.1603C>T (p.Arg535Cys)	ALDH6A1	Pathogenic	no assertion criteria provided
6617	NM_005589.4(ALDH6A1):c.1336G>A (p.Gly446Arg)	ALDH6A1	Pathogenic	no assertion criteria provided
915881	NM_005589.4(ALDH6A1):c.1261C>T (p.Pro421Ser)	ALDH6A1	Pathogenic	no assertion criteria provided
208070	NM_005589.4(ALDH6A1):c.785C>A (p.Ser262Tyr)	BBOF1	Pathogenic	no assertion criteria provided
208073	NM_005589.4(ALDH6A1):c.514T>C (p.Tyr172His)	BBOF1	Pathogenic	no assertion criteria provided
4849490	NM_005589.4(ALDH6A1):c.427C>T (p.Gln143Ter)	ALDH6A1	Likely pathogenic	criteria provided, single submitter
522934	NM_005589.4(ALDH6A1):c.1156C>T (p.Arg386Ter)	ALDH6A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
885007	NM_005589.4(ALDH6A1):c.759C>T (p.Asp253=)	ALDH6A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
886930	NM_005589.4(ALDH6A1):c.151T>C (p.Ser51Pro)	ALDH6A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
888129	NM_005589.4(ALDH6A1):c.921G>A (p.Gly307=)	ALDH6A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
888192	NM_005589.4(ALDH6A1):c.112-15G>T	ALDH6A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
872052	NM_005589.4(ALDH6A1):c.194A>G (p.Asn65Ser)	BBOF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
886931	NM_005589.4(ALDH6A1):c.145G>A (p.Val49Ile)	BBOF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1009082	NM_005589.4(ALDH6A1):c.827A>G (p.His276Arg)	ALDH6A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033011	NM_005589.4(ALDH6A1):c.1307A>G (p.Gln436Arg)	ALDH6A1	Uncertain significance	criteria provided, single submitter
1367704	NM_005589.4(ALDH6A1):c.878T>G (p.Met293Arg)	ALDH6A1	Uncertain significance	criteria provided, single submitter
1395079	NM_005589.4(ALDH6A1):c.919G>A (p.Gly307Arg)	ALDH6A1	Uncertain significance	criteria provided, single submitter
1419533	NM_005589.4(ALDH6A1):c.1373G>A (p.Arg458Gln)	ALDH6A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1708488	NM_005589.4(ALDH6A1):c.248T>C (p.Ile83Thr)	ALDH6A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2438975	NM_005589.4(ALDH6A1):c.349-3T>C	ALDH6A1	Uncertain significance	criteria provided, single submitter
3061947	NM_005589.4(ALDH6A1):c.1462C>T (p.Arg488Ter)	ALDH6A1	Uncertain significance	criteria provided, single submitter
314162	NM_005589.4(ALDH6A1):c.*377C>A	ALDH6A1	Uncertain significance	criteria provided, single submitter
314164	NM_005589.4(ALDH6A1):c.*234C>T	ALDH6A1	Uncertain significance	criteria provided, single submitter
314167	NM_005589.4(ALDH6A1):c.*43C>G	ALDH6A1	Uncertain significance	criteria provided, single submitter
314171	NM_005589.4(ALDH6A1):c.1400G>A (p.Gly467Glu)	ALDH6A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
314173	NM_005589.4(ALDH6A1):c.1221C>G (p.Val407=)	ALDH6A1	Uncertain significance	criteria provided, single submitter
314174	NM_005589.4(ALDH6A1):c.908A>G (p.Asn303Ser)	ALDH6A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
314176	NM_005589.4(ALDH6A1):c.799G>A (p.Glu267Lys)	ALDH6A1	Uncertain significance	criteria provided, single submitter
314182	NM_005589.4(ALDH6A1):c.189C>T (p.Ala63=)	ALDH6A1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ALDH6A1	Strong	Autosomal recessive	methylmalonate semialdehyde dehydrogenase deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALDH6A1	Orphanet:289307	Developmental delay due to methylmalonate semialdehyde dehydrogenase deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ALDH6A1	HGNC:7179	ENSG00000119711	Q02252	Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase [acylating], mitochondrial	gencc,clinvar
BBOF1	HGNC:19855	ENSG00000119636	Q8ND07	Basal body-orientation factor 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALDH6A1	Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase [acylating], mitochondrial	Malonate and methylmalonate semialdehyde dehydrogenase involved in the catabolism of valine, thymine, and compounds catabolized by way of beta-alanine, including uracil and cytidine.
BBOF1	Basal body-orientation factor 1	Plays an essential role in sperm motility and male fertility by stabilizing the sperm flagellar axonemal structure.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALDH6A1	Enzyme (other)	yes	1.2.1.18	MeMal-semiAld_DH, Aldehyde_DH_dom, Ald_DH_CS_CYS
BBOF1	Other/Unknown	no		DUF4515

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adult organism	1
nephron tubule	1
renal medulla	1
bronchial epithelial cell	1
bronchus	1
epithelium of bronchus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALDH6A1	293	ubiquitous	marker	adult organism, nephron tubule, renal medulla
BBOF1	258	ubiquitous	marker	bronchial epithelial cell, epithelium of bronchus, bronchus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDH6A1	1,906
BBOF1	588

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALDH6A1	Q02252	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BBOF1	Q8ND07	81.40

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Branched-chain amino acid catabolism	1	475.8×	0.006	ALDH6A1
Metabolism of amino acids and derivatives	1	67.6×	0.022	ALDH6A1
Metabolism	1	11.6×	0.086	ALDH6A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete valine metabolic process	1	8426.0×	7e-04	ALDH6A1
thymine metabolic process	1	8426.0×	7e-04	ALDH6A1
thymine catabolic process	1	2808.7×	0.001	ALDH6A1
L-valine catabolic process	1	1685.2×	0.002	ALDH6A1
branched-chain amino acid catabolic process	1	526.6×	0.005	ALDH6A1
motile cilium assembly	1	290.6×	0.006	BBOF1
negative regulation of microtubule depolymerization	1	247.8×	0.006	BBOF1
sperm axoneme assembly	1	234.1×	0.006	BBOF1
brown fat cell differentiation	1	216.1×	0.006	ALDH6A1
single fertilization	1	91.6×	0.013	BBOF1
flagellated sperm motility	1	58.5×	0.019	BBOF1
protein stabilization	1	33.4×	0.030	BBOF1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ALDH6A1	0	0
BBOF1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALDH6A1	1.2.1.18, 1.2.1.27	malonate-semialdehyde dehydrogenase (acetylating), methylmalonate-semialdehyde dehydrogenase (CoA-acylating)

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ALDH6A1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	BBOF1

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ALDH6A1	0	—
BBOF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.