ALDH6A1

Summary

ALDH6A1 (aldehyde dehydrogenase 6 family member A1, HGNC:7179) is a protein-coding gene on chromosome 14q24.3, encoding Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase [acylating], mitochondrial (Q02252). Malonate and methylmalonate semialdehyde dehydrogenase involved in the catabolism of valine, thymine, and compounds catabolized by way of beta-alanine, including uracil and cytidine.

This gene encodes a member of the aldehyde dehydrogenase protein family. The encoded protein is a mitochondrial methylmalonate semialdehyde dehydrogenase that plays a role in the valine and pyrimidine catabolic pathways. This protein catalyzes the irreversible oxidative decarboxylation of malonate and methylmalonate semialdehydes to acetyl- and propionyl-CoA. Methylmalonate semialdehyde dehydrogenase deficiency is characterized by elevated beta-alanine, 3-hydroxypropionic acid, and both isomers of 3-amino and 3-hydroxyisobutyric acids in urine organic acids. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 4329 — RefSeq curated summary.

At a glance

• Gene–disease (curated): methylmalonate semialdehyde dehydrogenase deficiency (Strong, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 233 total — 5 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 40
• MANE Select transcript: NM_005589

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7179
Approved symbol	ALDH6A1
Name	aldehyde dehydrogenase 6 family member A1
Location	14q24.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000119711
Ensembl biotype	protein_coding
OMIM	603178
Entrez	4329

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 12 protein_coding, 2 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000350259, ENST00000553458, ENST00000553814, ENST00000554231, ENST00000554501, ENST00000555126, ENST00000556852, ENST00000901407, ENST00000901408, ENST00000901409, ENST00000901410, ENST00000901411, ENST00000901412, ENST00000901413, ENST00000931795, ENST00000960461

RefSeq mRNA: 3 — MANE Select: NM_005589 NM_001278593, NM_001278594, NM_005589

CCDS: CCDS61501, CCDS9826

Canonical transcript exons

ENST00000553458 — 12 exons

Exon	Start	End
ENSE00000808099	74071195	74071497
ENSE00001378933	74084347	74084453
ENSE00002502741	74056847	74060746
ENSE00003465336	74071896	74071974
ENSE00003466023	74068860	74068981
ENSE00003487593	74064822	74064920
ENSE00003513907	74074955	74075017
ENSE00003571549	74072537	74072611
ENSE00003594336	74065181	74065360
ENSE00003608555	74067380	74067569
ENSE00003617404	74066705	74066886
ENSE00003690409	74072203	74072364

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 99.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.0138 / max 369.2339, expressed in 1777 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
144012	17.6606	1777
144013	0.3532	162

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adult organism	UBERON:0007023	99.30	gold quality
nephron tubule	UBERON:0001231	99.17	gold quality
renal medulla	UBERON:0000362	98.93	gold quality
kidney epithelium	UBERON:0004819	98.80	gold quality
renal glomerulus	UBERON:0000074	98.29	gold quality
lateral globus pallidus	UBERON:0002476	98.27	gold quality
metanephric glomerulus	UBERON:0004736	98.12	gold quality
liver	UBERON:0002107	98.05	gold quality
endothelial cell	CL:0000115	98.04	gold quality
cranial nerve II	UBERON:0000941	97.94	gold quality
inferior vagus X ganglion	UBERON:0005363	97.34	gold quality
subthalamic nucleus	UBERON:0001906	97.21	gold quality
adult mammalian kidney	UBERON:0000082	97.05	gold quality
ventral tegmental area	UBERON:0002691	96.93	gold quality
entorhinal cortex	UBERON:0002728	96.82	gold quality
right lobe of liver	UBERON:0001114	96.80	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	96.74	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.72	gold quality
globus pallidus	UBERON:0001875	96.46	gold quality
kidney	UBERON:0002113	96.41	gold quality
postcentral gyrus	UBERON:0002581	96.24	gold quality
medulla oblongata	UBERON:0001896	96.17	gold quality
parietal lobe	UBERON:0001872	96.10	gold quality
dorsal plus ventral thalamus	UBERON:0001897	96.09	gold quality
CA1 field of hippocampus	UBERON:0003881	96.06	gold quality
substantia nigra pars compacta	UBERON:0001965	95.99	gold quality
medial globus pallidus	UBERON:0002477	95.99	gold quality
corpus callosum	UBERON:0002336	95.88	gold quality
choroid plexus epithelium	UBERON:0003911	95.86	gold quality
pigmented layer of retina	UBERON:0001782	95.83	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	36.12
E-ANND-3	yes	15.88

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HNF4A

miRNA regulators (miRDB)

173 targeting ALDH6A1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-5680	99.91	69.83	3421

Literature-anchored findings (GeneRIF, showing 7)

• Mutation analysis in the ALDH6A1 gene can reveal a cause of 3-hydroxyisobutyric aciduria, which may present with only slightly increased urinary levels of 3-hydroxyisobutyric acid, if a patient is metabolically stable [case reports] (PMID:21863277)
• ACAT1, ACACA, ALDH6A1 and MTHFD1 represent novel biomarkers in adipose tissue associated with type 2 diabetes in obese individuals. (PMID:25099943)
• Results show that ALDH6A1 expression is significantly reduced in metastatic prostate cancer and represents a strong marker predicting survival, along with HSP27 and prohibitin. (PMID:30396985)
• Identification of ALDH6A1 as a Potential Molecular Signature in Hepatocellular Carcinoma via Quantitative Profiling of the Mitochondrial Proteome. (PMID:31985234)
• Identification and validation of a two-gene metabolic signature for survival prediction in patients with kidney renal clear cell carcinoma. (PMID:33686951)
• ALDH6A1 weakens the progression of colon cancer via modulating the RAS/RAF/MEK/ERK pathway in cancer cell lines. (PMID:35907565)
• The downregulated drug-metabolism related ALDH6A1 serves as predictor for prognosis and therapeutic immune response in gastric cancer. (PMID:36098688)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	aldh6a1	ENSDARG00000053485
mus_musculus	Aldh6a1	ENSMUSG00000021238
rattus_norvegicus	Aldh6a1	ENSRNOG00000011419
drosophila_melanogaster	CG17896	FBGN0023537
caenorhabditis_elegans		WBGENE00000114

Paralogs (17): ALDH3B1 (ENSG00000006534), ALDH3A2 (ENSG00000072210), ALDH3A1 (ENSG00000108602), ALDH2 (ENSG00000111275), ALDH5A1 (ENSG00000112294), ALDH8A1 (ENSG00000118514), ALDH1A2 (ENSG00000128918), ALDH3B2 (ENSG00000132746), ALDH1L2 (ENSG00000136010), ALDH1B1 (ENSG00000137124), ALDH9A1 (ENSG00000143149), ALDH1L1 (ENSG00000144908), ALDH4A1 (ENSG00000159423), ALDH16A1 (ENSG00000161618), ALDH7A1 (ENSG00000164904), ALDH1A1 (ENSG00000165092), ALDH1A3 (ENSG00000184254)

Protein

Protein identifiers

Methylmalonate-semialdehyde/malonate-semialdehyde dehydrogenase [acylating], mitochondrial — Q02252 (reviewed: Q02252)

Alternative names: Aldehyde dehydrogenase family 6 member A1, Malonate-semialdehyde dehydrogenase [acylating]

All UniProt accessions (3): A0A024R6G4, Q02252, G3V4Z4

UniProt curated annotations — full annotation on UniProt →

Function. Malonate and methylmalonate semialdehyde dehydrogenase involved in the catabolism of valine, thymine, and compounds catabolized by way of beta-alanine, including uracil and cytidine.

Subunit / interactions. Homotetramer.

Subcellular location. Mitochondrion.

Disease relevance. Methylmalonate semialdehyde dehydrogenase deficiency (MMSDHD) [MIM:614105] A metabolic disorder characterized by elevated beta-alanine, 3-hydroxypropionic acid, and both isomers of 3-amino and 3-hydroxyisobutyric acids in urine organic acids. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the aldehyde dehydrogenase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q02252-1	1	yes
Q02252-2	2

RefSeq proteins (3): NP_001265522, NP_001265523, NP_005580* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010061	MeMal-semiAld_DH	Family
IPR015590	Aldehyde_DH_dom	Domain
IPR016160	Ald_DH_CS_CYS	Conserved_site
IPR016161	Ald_DH/histidinol_DH	Homologous_superfamily
IPR016162	Ald_DH_N	Homologous_superfamily
IPR016163	Ald_DH_C	Homologous_superfamily

Pfam: PF00171

Enzyme classification (BRENDA):

• EC 1.2.1.18 — malonate-semialdehyde dehydrogenase (acetylating) (BRENDA: 7 organisms, 11 substrates, 4 inhibitors, 7 Km, 0 kcat entries)
• EC 1.2.1.27 — methylmalonate-semialdehyde dehydrogenase (CoA-acylating) (BRENDA: 11 organisms, 31 substrates, 9 inhibitors, 54 Km, 20 kcat entries)

Substrate kinetics (BRENDA)

12 substrates with measured Km, best-characterized 12. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
COA	0.021–0.62	16
NAD+	0.033–9.44	15
METHYLMALONATE SEMIALDEHYDE	0.006–0.215	10
2-METHYL-3-OXOPROPANOATE	0.0025–0.06	5
3-OXOPROPANOATE	0.0045–0.05	2
COA	0.03–0.1	2
NAD+	0.15–0.2	2
2-MERCAPTOETHANOL	0.54–44	2
PROPANAL	6.1–6.4	2
PROPIONALDEHYDE	9.3–9.8	2
2-METHYL-3-OXOPROPANOATE	0.0053	1
MALONATE SEMIALDEHYDE	0.0045	1

Catalyzed reactions (Rhea), 4 shown:

• 2-methyl-3-oxopropanoate + NAD(+) + CoA + H2O = propanoyl-CoA + hydrogencarbonate + NADH + H(+) (RHEA:20804)
• 3-oxopropanoate + NAD(+) + CoA + H2O = hydrogencarbonate + acetyl-CoA + NADH + H(+) (RHEA:76615)
• (R)-2-methyl-3-oxopropanoate + NAD(+) + CoA + H2O = propanoyl-CoA + hydrogencarbonate + NADH + H(+) (RHEA:76623)
• (S)-2-methyl-3-oxopropanoate + NAD(+) + CoA + H2O = propanoyl-CoA + hydrogencarbonate + NADH + H(+) (RHEA:76627)

UniProt features (90 total): modified residue 25, strand 25, helix 20, binding site 7, sequence variant 3, sequence conflict 3, turn 3, transit peptide 1, chain 1, active site 1, splice variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8XXQ	ELECTRON MICROSCOPY	2.75
9IZX	ELECTRON MICROSCOPY	3
9IZV	ELECTRON MICROSCOPY	3.02
9IZW	ELECTRON MICROSCOPY	3.12
9IZU	ELECTRON MICROSCOPY	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q02252-F1	93.98	0.90

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 317 (nucleophile)

Ligand- & substrate-binding residues (7): 183; 185; 209; 212; 213; 262; 417

Post-translational modifications (25): 47, 47, 52, 52, 55, 55, 76, 76, 87, 117, 117, 129, 129, 262, 298, 330, 331, 364, 364, 376 …

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-70895	Branched-chain amino acid catabolism
R-HSA-1430728	Metabolism
R-HSA-71291	Metabolism of amino acids and derivatives

MSigDB gene sets: 366 (showing top): E2F_Q4, MODULE_93, KOBAYASHI_EGFR_SIGNALING_24HR_UP, E2F4DP1_01, GGGNRMNNYCAT_UNKNOWN, CMYB_01, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, SARRIO_EPITHELIAL_MESENCHYMAL_TRANSITION_DN, GOBP_PYRIMIDINE_NUCLEOBASE_METABOLIC_PROCESS, KEGG_VALINE_LEUCINE_AND_ISOLEUCINE_DEGRADATION, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, COUP_01, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, FERREIRA_EWINGS_SARCOMA_UNSTABLE_VS_STABLE_DN, GOBP_PYRIMIDINE_CONTAINING_COMPOUND_CATABOLIC_PROCESS

GO Biological Process (6): thymine catabolic process (GO:0006210), obsolete valine metabolic process (GO:0006573), L-valine catabolic process (GO:0006574), branched-chain amino acid catabolic process (GO:0009083), thymine metabolic process (GO:0019859), brown fat cell differentiation (GO:0050873)

GO Molecular Function (5): RNA binding (GO:0003723), methylmalonate-semialdehyde dehydrogenase (acylating, NAD) activity (GO:0004491), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the aldehyde or oxo group of donors, NAD or NADP as acceptor (GO:0016620), malonate-semialdehyde dehydrogenase (acetylating) activity (GO:0018478)

GO Cellular Component (3): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
oxidoreductase activity, acting on the aldehyde or oxo group of donors, NAD or NADP as acceptor	2
pyrimidine nucleobase catabolic process	1
thymine metabolic process	1
branched-chain amino acid catabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
amino acid catabolic process	1
branched-chain amino acid metabolic process	1
carboxylic acid catabolic process	1
pyrimidine nucleobase metabolic process	1
fat cell differentiation	1
nucleic acid binding	1
catalytic activity	1
oxidoreductase activity, acting on the aldehyde or oxo group of donors	1
nuclear lumen	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

1788 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALDH6A1	HIBADH	P31937	683
ALDH6A1	HIBCH	Q6NVY1	667
ALDH6A1	ECHS1	P30084	645
ALDH6A1	ACADSB	P45954	637
ALDH6A1	ALDH18A1	P54886	627
ALDH6A1	ABAT	P80404	573
ALDH6A1	BCKDHB	P21953	545
ALDH6A1	ADHFE1	Q8IWW8	544
ALDH6A1	PCCB	P05166	532
ALDH6A1	IVD	P26440	518
ALDH6A1	BCAT2	O15382	501
ALDH6A1	ACAA2	P42765	494
ALDH6A1	HMGCL	P35914	478
ALDH6A1	ACAD8	Q9UKU7	471
ALDH6A1	PCCA	P05165	464

IntAct

45 interactions, top by confidence:

A	B	Type	Score
POLG2	POLG	psi-mi:“MI:0914”(association)	0.950
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
ABRAXAS1	LAMC1	psi-mi:“MI:0914”(association)	0.530
POLG2	GLDC	psi-mi:“MI:0914”(association)	0.530
ALDH8A1	ALDH6A1	psi-mi:“MI:0914”(association)	0.530
COX5B	COX7A2L	psi-mi:“MI:0914”(association)	0.530
CYP1A1	SNX3	psi-mi:“MI:0914”(association)	0.530
ALDH6A1		psi-mi:“MI:0915”(physical association)	0.370
LMO2	ALDH6A1	psi-mi:“MI:0915”(physical association)	0.370
LAMP2	HSPA12A	psi-mi:“MI:0914”(association)	0.350
ALDH2	ALDH1A2	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
PTCD1	VWA8	psi-mi:“MI:0914”(association)	0.350
HOXC5	PDLIM1	psi-mi:“MI:0914”(association)	0.350
RPL35A	SMCHD1	psi-mi:“MI:0914”(association)	0.350
DEFB136	MANBA	psi-mi:“MI:0914”(association)	0.350
RABIF	RAD21	psi-mi:“MI:0914”(association)	0.350
BEX4	KLHL41	psi-mi:“MI:0914”(association)	0.350
OR1D4	FZD7	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
FAHD1	VWA8	psi-mi:“MI:0914”(association)	0.350
SLC25A16	TOMM70	psi-mi:“MI:0914”(association)	0.350

BioGRID (73): ALDH6A1 (Affinity Capture-MS), ALDH6A1 (Affinity Capture-MS), ALDH4A1 (Co-fractionation), ALDH6A1 (Co-fractionation), ALDH6A1 (Co-fractionation), ALDH6A1 (Co-fractionation), FAXC (Co-fractionation), GSTK1 (Co-fractionation), GYG2 (Co-fractionation), HSPE1 (Co-fractionation), PITPNB (Co-fractionation), TPI1 (Co-fractionation), ALDH6A1 (Affinity Capture-MS), ALDH6A1 (Affinity Capture-MS), ALDH6A1 (Affinity Capture-MS)

ESM2 similar proteins: A7YWE4, O74766, O75891, P07275, P0C2X9, P25795, P28037, P30038, P46562, P49419, P51649, P51650, P54889, P78568, P83401, Q02252, Q02253, Q07536, Q0WM29, Q141D3, Q1GV29, Q29HB2, Q2KJC9, Q2SKP1, Q3MSM3, Q3MSM4, Q3SY69, Q41247, Q54RA2, Q5RFM9, Q64057, Q6A2H0, Q6A2H1, Q6A2H2, Q6JQN1, Q7KW39, Q7QC84, Q7SY23, Q802W2, Q8BWF0

Diamond homologs: A0RDW1, A0REB5, A3M365, A4IPB2, A4IPF5, A5YBJ3, A6W2P7, A7BJC4, A7GPH3, A7ZAI1, A8FDV4, A9VF06, A9VMS6, B0V944, B2HV80, B3PTE1, B5ZUG3, B7GYG4, B7H597, B7HR31, B7I896, B7IW48, B8DCT8, B9IZZ7, B9JBA3, C1KZ99, D4GP41, E1V7V8, O06837, O14293, O34660, O35945, P05091, P11884, P28810, P30837, P42236, P42329, P42412, P46367

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

233 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	2
Uncertain significance	114
Likely benign	63
Benign	31

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
208071	NM_005589.4(ALDH6A1):c.184C>T (p.Pro62Ser)	Pathogenic
208072	NM_005589.4(ALDH6A1):c.1603C>T (p.Arg535Cys)	Pathogenic
3244015	NC_000014.8:g.(?74111743)(74551097_?)del	Pathogenic
6617	NM_005589.4(ALDH6A1):c.1336G>A (p.Gly446Arg)	Pathogenic
915881	NM_005589.4(ALDH6A1):c.1261C>T (p.Pro421Ser)	Pathogenic
445855	NM_005589.4(ALDH6A1):c.1306del (p.Gln436fs)	Likely pathogenic
4849490	NM_005589.4(ALDH6A1):c.427C>T (p.Gln143Ter)	Likely pathogenic

SpliceAI

2249 predictions. Top by Δscore:

Variant	Effect	Δscore
14:74057134:A:AG	acceptor_gain	1.0000
14:74057139:T:A	acceptor_gain	1.0000
14:74057142:A:AG	acceptor_gain	1.0000
14:74057142:AG:A	acceptor_gain	1.0000
14:74057142:AGG:A	acceptor_gain	1.0000
14:74057143:G:GA	acceptor_gain	1.0000
14:74057143:GG:G	acceptor_gain	1.0000
14:74057143:GGG:G	acceptor_gain	1.0000
14:74057143:GGGAT:G	acceptor_gain	1.0000
14:74057210:TG:T	donor_gain	1.0000
14:74057254:ACACA:A	donor_gain	1.0000
14:74057255:CACA:C	donor_gain	1.0000
14:74057256:ACA:A	donor_gain	1.0000
14:74057257:CA:C	donor_gain	1.0000
14:74057257:CAGTA:C	donor_loss	1.0000
14:74057258:AGTAA:A	donor_loss	1.0000
14:74057259:G:GG	donor_gain	1.0000
14:74057259:GTA:G	donor_loss	1.0000
14:74057260:T:A	donor_loss	1.0000
14:74057263:GGA:G	donor_gain	1.0000
14:74057264:GAG:G	donor_gain	1.0000
14:74057266:G:GG	donor_gain	1.0000
14:74060607:A:AC	donor_gain	1.0000
14:74060608:C:CC	donor_gain	1.0000
14:74060634:A:AC	donor_gain	1.0000
14:74060635:C:CC	donor_gain	1.0000
14:74064817:GTTA:G	donor_loss	1.0000
14:74064818:TTA:T	donor_loss	1.0000
14:74064819:TACCT:T	donor_loss	1.0000
14:74064820:A:T	donor_loss	1.0000

AlphaMissense

3482 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:74071364:A:C	F187L	1.000
14:74071364:A:T	F187L	1.000
14:74071366:A:G	F187L	1.000
14:74071367:A:C	N186K	1.000
14:74071367:A:T	N186K	1.000
14:74064873:G:C	F484L	0.999
14:74064873:G:T	F484L	0.999
14:74064875:A:G	F484L	0.999
14:74065250:A:C	N445K	0.999
14:74065250:A:T	N445K	0.999
14:74065328:A:C	F419L	0.999
14:74065328:A:T	F419L	0.999
14:74065330:A:G	F419L	0.999
14:74067558:G:C	N288K	0.999
14:74067558:G:T	N288K	0.999
14:74068930:C:T	G261E	0.999
14:74068938:G:C	S258R	0.999
14:74068938:G:T	S258R	0.999
14:74068940:T:G	S258R	0.999
14:74071317:C:A	G203V	0.999
14:74071345:A:G	W194R	0.999
14:74071345:A:T	W194R	0.999
14:74071365:A:C	F187C	0.999
14:74071370:G:C	F185L	0.999
14:74071370:G:T	F185L	0.999
14:74071372:A:G	F185L	0.999
14:74071923:C:G	A134P	0.999
14:74065235:G:C	F450L	0.998
14:74065235:G:T	F450L	0.998
14:74065237:A:G	F450L	0.998

dbSNP variants (sampled 300 via entrez): RS1000086842 (14:74064607 T>C), RS1000191651 (14:74079066 C>T), RS1000222607 (14:74079357 C>T), RS1000288820 (14:74077360 G>A), RS1000338604 (14:74069850 C>T), RS1000349594 (14:74085261 C>T), RS1000506543 (14:74078693 A>G), RS1000529127 (14:74077355 A>G), RS1000575797 (14:74076982 T>C), RS1000615415 (14:74070575 A>G), RS1000724324 (14:74084465 C>G,T), RS1000782752 (14:74085558 G>T), RS1000786842 (14:74063322 G>A), RS1000851927 (14:74064191 G>A), RS1001025223 (14:74078935 G>T)

Disease associations

OMIM: gene MIM:603178 | disease phenotypes: MIM:614105, MIM:614017

GenCC curated gene-disease

Disease	Classification	Inheritance
methylmalonate semialdehyde dehydrogenase deficiency	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
methylmalonate semialdehyde dehydrogenase deficiency	Limited	AR

Mondo (2): methylmalonate semialdehyde dehydrogenase deficiency (MONDO:0013579), primary ciliary dyskinesia 16 (MONDO:0013525)

Orphanet (2): Developmental delay due to methylmalonate semialdehyde dehydrogenase deficiency (Orphanet:289307), Primary ciliary dyskinesia (Orphanet:244)

HPO phenotypes

40 total (30 of 40 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000343	Long philtrum
HP:0000348	High forehead
HP:0000414	Bulbous nose
HP:0000463	Anteverted nares
HP:0000494	Downslanted palpebral fissures
HP:0000518	Cataract
HP:0000568	Microphthalmia
HP:0000954	Single transverse palmar crease
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001332	Dystonia
HP:0001942	Metabolic acidosis
HP:0002007	Frontal bossing
HP:0002079	Hypoplasia of the corpus callosum
HP:0002151	Increased circulating lactate concentration
HP:0002188	Delayed CNS myelination
HP:0002912	Methylmalonic acidemia
HP:0003196	Short nose
HP:0003593	Infantile onset
HP:0005280	Depressed nasal bridge
HP:0006956	Lateral ventricle dilatation
HP:0007165	Periventricular heterotopia
HP:0007814	Retinal pigment epithelial mottling
HP:0008070	Sparse hair

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004621_72	Red cell distribution width	5.000000e-44
GCST010002_156	Refractive error	7.000000e-25
GCST90002403_515	Red blood cell count	9.000000e-14

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009188	Red cell distribution width
EFO:0004305	erythrocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C566402	Methylmalonate Semialdehyde Dehydrogenase Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

80 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression	4
bisphenol A	affects expression, decreases expression, increases expression	3
Air Pollutants	decreases expression, affects expression, increases abundance	3
Benzo(a)pyrene	decreases expression	3
Hydrogen Peroxide	affects expression, increases expression	3
Aflatoxin B1	affects expression, decreases expression	3
Cadmium Chloride	decreases expression, increases expression	3
sodium arsenite	increases expression, affects expression, increases abundance	2
Acetaminophen	decreases expression	2
Nickel	decreases expression	2
Silicon Dioxide	decreases expression	2
Smoke	decreases expression, increases abundance	2
Valproic Acid	affects expression, decreases expression	2
aristolochic acid I	decreases expression	1
afuresertib	increases expression	1
bisphenol F	increases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
deoxynivalenol	decreases expression	1
glycidyl methacrylate	decreases expression	1
senecionine	increases expression	1
senkirkine	decreases expression	1
heliotrine	decreases expression	1
2-methyl-4-isothiazolin-3-one	decreases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
periodate-oxidized adenosine	affects expression	1
beta-methylcholine	affects expression	1
pentanal	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.