SHMT2 (P34897) variants and mutations
SHMT2 (also known as P34897) is a human protein-coding gene encoding a serine hydroxymethyltransferase, mitochondrial protein. It transfers one-carbon units from serine into the mitochondrial folate cycle while generating glycine, supporting nucleotide synthesis, redox balance, and mitochondrial translation. Altered activity is important in proliferating and metabolically stressed cells, including many cancers. This analysis covers 702 SHMT2 variants and mutations. Of these, 89% have computational variant effect predictions. Disease context includes neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormali, microcephaly, and polymicrogyria. Example SHMT2 variants include L2L, Y3C, and Y3T.
Variant analysis overview
- Gene: SHMT2
- Protein: P34897
- UniProt accession: P34897
- Organism: Homo sapiens
- Variants analyzed: 702
- Variant scope: all variants
- Completed: 2026-08-06
Variant and mutation evidence
- Variant composition: 502 unspecified-consequence records; 93 synonymous variants; 14 frameshift variants; 79 missense variants; 2 splice-region variants; 7 stop-gained variants; 2 in-frame deletions; 3 substitution
- Prediction scores: 624 variants have prediction scores (89% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormali, microcephaly, polymicrogyria, neurodevelopmental disorder, hereditary disease, schizophrenia, neoplasm, breast carcinoma, breast cancer, autism spectrum disorder, gastric cancer, colorectal carcinoma.
Protein structure and variant hotspots
- Protein features: 11 post-translational modification sites.
- PTM context: 9 variants overlap post-translational modification sites.
Data sources
Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, 3D Hotspot Analysis, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, MaveDB, LitVar.
Notable SHMT2 variants
Examples include L2L, Y3C, Y3T, Y3Y, F4L, S5T, S5F, S5S. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- L2L (p.Leu2Leu), gnomAD 12-57229782-C-T, CADD 9.84
- Y3C (p.Tyr3Cys), TOPMed rs2037237805, REVEL 0.17, CADD 14.50
- Y3T (p.Tyr3Thr), gnomAD 12-57229784-GT-G, CADD 15.30
- Y3Y (p.Tyr3Tyr), rs544008349, gnomAD 12-57229787-C-T, CADD 4.98
- F4L (p.Phe4Leu), Ensembl rs1018328554, REVEL 0.26, CADD 13.00
- S5T (p.Ser5Thr), gnomAD 12-57229791-T-A, REVEL 0.06, CADD 13.90
- S5F (p.Ser5Phe), gnomAD 12-57229792-C-T, REVEL 0.20, CADD 22.70
- S5S (p.Ser5Ser), rs754466364, gnomAD 12-57229793-T-G, CADD 13.60
- L6V (p.Leu6Val), gnomAD 12-57229792-CTT-C, CADD 23.30
- L6L (p.Leu6Leu), rs143150683, gnomAD 12-57229794-T-C, CADD 14.30
- L6F (p.Leu6Phe), gnomAD 12-57229796-G-C, REVEL 0.03, CADD 7.48
- F7L (p.Phe7Leu), Ensembl rs940454853
- W8C (p.Trp8Cys), gnomAD rs1288927296, REVEL 0.14, CADD 20.70
- W8R (p.Trp8Arg), cosmic curated COSV10733, TOPMed rs1247786813, gnomAD rs1247786813, REVEL 0.24, CADD 8.82
- W8G (p.Trp8Gly), rs764141971, gnomAD 12-57229796-GT-G, CADD 14.10
- A9E (p.Ala9Glu), ExAC rs747807742, gnomAD rs747807742, REVEL 0.19, CADD 12.40
- A10V (p.Ala10Val), TOPMed rs1321687419
- A10A (p.Ala10Ala), gnomAD 12-57229808-T-G, CADD 14.10
- R11P (p.Arg11Pro), gnomAD rs1234551409, REVEL 0.19, CADD 22.40
- R11W (p.Arg11Trp), cosmic curated COSV61072, gnomAD rs1205082451, REVEL 0.13, CADD 26.80
- P12L (p.Pro12Leu), gnomAD 12-57230804-C-T, REVEL 0.28, CADD 31.00
- P12P (p.Pro12Pro), gnomAD 12-57230805-T-G, CADD 15.30
- L13P (p.Leu13Pro), gnomAD rs1487312566, REVEL 0.19, CADD 26.00
- L13L (p.Leu13Leu), gnomAD 12-57230808-G-T, CADD 9.62
- Q14E (p.Gln14Glu), Ensembl rs2037283459
- Q14R (p.Gln14Arg), TOPMed rs1292619200, REVEL 0.06, CADD 10.90
- R15I (p.Arg15Ile), NCI-TCGA Cosmic COSV6107, cosmic curated COSV61073, Variant assessed as somatic; moderate impact.
- R15T (p.Arg15Thr), gnomAD 12-57230813-G-C, REVEL 0.12, CADD 23.80
- C16Y (p.Cys16Tyr), gnomAD rs1216006197, REVEL 0.18, CADD 22.30
- G17E (p.Gly17Glu), TOPMed rs2037283671
- G17G (p.Gly17Gly), gnomAD 12-57230820-G-A, CADD 6.30
- L19P (p.Leu19Pro), TOPMed rs1333432063, gnomAD rs1333432063, REVEL 0.21, CADD 22.90
- L19G (p.Leu19Gly), rs1233392204, gnomAD 12-57230823-GCT-G, CADD 29.10
- L19V (p.Leu19Val), gnomAD 12-57230824-C-G, REVEL 0.06, CADD 18.80
- L19L (p.Leu19Leu), rs1565769044, gnomAD 12-57230824-C-T, CADD 12.80
- V20L (p.Val20Leu), gnomAD 12-57230827-G-C, REVEL 0.07, CADD 18.10
- V20I (p.Val20Ile), gnomAD 12-57230827-G-A, REVEL 0.03, CADD 18.60
- V20V (p.Val20Val), rs1291071672, gnomAD 12-57230829-C-G, CADD 9.61
- R21S (p.Arg21Ser), TOPMed rs1453830388, gnomAD rs1453830388, REVEL 0.06, CADD 17.40
- R21T (p.Arg21Thr), ExAC rs777502493, gnomAD rs777502493, REVEL 0.13, CADD 16.60
- R21W (p.Arg21Trp), gnomAD 12-57230830-A-T, REVEL 0.09, CADD 18.10
- A23D (p.Ala23Asp), TOPMed rs1401525851, gnomAD rs1401525851, REVEL 0.17, CADD 21.80
- A23V (p.Ala23Val), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- A23T (p.Ala23Thr), gnomAD 12-57230836-G-A, REVEL 0.08, CADD 22.70
- I24L (p.Ile24Leu), gnomAD rs2037284991, REVEL 0.02, AlphaMissense 0.08
- I24T (p.Ile24Thr), cosmic curated COSV61074, 1000Genomes rs138045473, ExAC rs138045473, TOPMed rs138045473, REVEL 0.10, CADD 5.93
- I24V (p.Ile24Val), rs2037284991, ClinGen CA385468782, ClinVar RCV002992850, AlphaMissense 0.08, MetaLR 0.03, Uncertain significance, Inborn genetic diseases
- I24I (p.Ile24Ile), gnomAD 12-57230841-T-C, CADD 6.18
- R25Q (p.Arg25Gln), rs375322221, NCI-TCGA Cosmic COSV1001, cosmic curated COSV61074, ESP rs375322221, REVEL 0.12, CADD 22.80, Uncertain significance, Inborn genetic diseases; Neurodevelopmental disorder with cardiomyopathy, spasti
- R25W (p.Arg25Trp), rs117173238, ClinGen CA6646257, ClinVar RCV003252734, 1000Genomes rs117173238, REVEL 0.18, CADD 24.10, Uncertain significance, Inborn genetic diseases
- A26S (p.Ala26Ser), rs112251410, ClinGen CA385468810, ClinVar RCV004451196, AlphaMissense 0.09, MetaLR 0.03, Uncertain significance, Inborn genetic diseases
- A26T (p.Ala26Thr), rs112251410, gnomAD rs112251410, REVEL 0.03, AlphaMissense 0.09, Variant assessed as somatic; moderate impact.
- A26V (p.Ala26Val), gnomAD 12-57230846-C-T, REVEL 0.05, CADD 21.70
- Q27H (p.Gln27His), TOPMed rs1165343011, REVEL 0.17, CADD 21.20
- Q27P (p.Gln27Pro), gnomAD 12-57230849-A-C, REVEL 0.22, CADD 22.90
- Q27R (p.Gln27Arg), gnomAD 12-57230849-A-G, REVEL 0.15, CADD 22.40
- H28H (p.His28His), gnomAD 12-57230853-C-T, CADD 13.70
- S29G (p.Ser29Gly), ExAC rs778622265, TOPMed rs778622265, gnomAD rs778622265, REVEL 0.04, CADD 21.30
- S29R (p.Ser29Arg), ExAC rs778622265, TOPMed rs778622265, gnomAD rs778622265, REVEL 0.04, CADD 22.10
- N30K (p.Asn30Lys), rs771968637, ClinGen CA385468889, ClinVar RCV002992650, ExAC rs771968637, REVEL 0.01, CADD 6.97, Likely benign, Inborn genetic diseases
- N30T (p.Asn30Thr), TOPMed rs2037285975, gnomAD rs2037285975, REVEL 0.02, CADD 17.60
- N30S (p.Asn30Ser), gnomAD 12-57230854-AGCAA, CADD 26.20
- N30N (p.Asn30Asn), rs771968637, gnomAD 12-57230859-C-T, CADD 8.95
- A31T (p.Ala31Thr), 1000Genomes rs202041947, ESP rs202041947, ExAC rs202041947, TOPMed rs202041947, REVEL 0.04, CADD 22.80, Uncertain significance, Inborn genetic diseases
- A31V (p.Ala31Val), gnomAD 12-57230861-C-T, REVEL 0.05, CADD 20.10
- A31A (p.Ala31Ala), gnomAD 12-57230862-A-C, CADD 8.96
- A32D (p.Ala32Asp), Ensembl rs1565769175, REVEL 0.15, CADD 22.30
- A32P (p.Ala32Pro), gnomAD 12-57230863-G-C, REVEL 0.15, CADD 23.70
- A32T (p.Ala32Thr), gnomAD 12-57230863-G-A, REVEL 0.13, CADD 23.40
- A32A (p.Ala32Ala), rs1366965602, gnomAD 12-57230865-C-T, CADD 14.50
- Q33E (p.Gln33Glu), NCI-TCGA Cosmic COSV1001, NCI-TCGA Cosmic COSV6107, cosmic curated COSV61073, REVEL 0.07, CADD 15.40, Variant assessed as somatic; moderate impact.
- Q33R (p.Gln33Arg), gnomAD 12-57230867-A-G, REVEL 0.03, CADD 17.80
- Q33Q (p.Gln33Gln), rs2136784404, gnomAD 12-57230868-G-A, CADD 13.30
- T34P (p.Thr34Pro), gnomAD 12-57230869-A-C, REVEL 0.06, CADD 21.30
- Q35E (p.Gln35Glu), ExAC rs747029667, gnomAD rs747029667, REVEL 0.04, CADD 14.60
- Q35L (p.Gln35Leu), ExAC rs768724103, gnomAD rs768724103, REVEL 0.04, CADD 17.40
- T36N (p.Thr36Asn), gnomAD 12-57230876-C-A, REVEL 0.01, CADD 15.60
- T36T (p.Thr36Thr), rs776789647, gnomAD 12-57230877-T-C, CADD 12.70
- G37E (p.Gly37Glu), gnomAD 12-57230879-G-A, REVEL 0.06, CADD 18.80
- E38K (p.Glu38Lys), TOPMed rs2037286969
- N40D (p.Asn40Asp), gnomAD 12-57230887-A-G, REVEL 0.01, CADD 7.77
- N40K (p.Asn40Lys), gnomAD 12-57230889-C-A, REVEL 0.01, CADD 7.14
- R41K (p.Arg41Lys), Ensembl rs2037287356
- R41G (p.Arg41Gly), rs761732423, gnomAD 12-57230889-CAG-C, CADD 22.30
- R41R (p.Arg41Arg), rs200843046, gnomAD 12-57230892-G-A, CADD 8.33
- G42V (p.Gly42Val), gnomAD 12-57230894-G-T, REVEL 0.06, CADD 21.90
- G42G (p.Gly42Gly), rs369518884, gnomAD 12-57230895-C-T, CADD 11.50
- W43G (p.Trp43Gly), Ensembl rs2037287824
- T44R (p.Thr44Arg), TOPMed rs1292550437, gnomAD rs1292550437, REVEL 0.15, CADD 23.20
- T44S (p.Thr44Ser), gnomAD rs1239781364, REVEL 0.05, CADD 21.50
- G45G (p.Gly45Gly), rs1358623780, gnomAD 12-57230904-C-T, CADD 15.70
- Q46Q (p.Gln46Gln), rs1208525071, gnomAD 12-57230907-G-A, CADD 11.00
- E47E (p.Glu47Glu), gnomAD 12-57230910-G-A, CADD 13.30
- S48N (p.Ser48Asn), gnomAD rs1267305911, REVEL 0.04, CADD 19.70
- S48R (p.Ser48Arg), 1000Genomes rs183592454, ExAC rs183592454, TOPMed rs183592454, gnomAD rs183592454, REVEL 0.08, CADD 11.20
- S48G (p.Ser48Gly), gnomAD 12-57230911-A-G, REVEL 0.05, CADD 22.70
- L49Q (p.Leu49Gln), Ensembl rs1468417532
- L49L (p.Leu49Leu), rs763506557, gnomAD 12-57230914-C-T, CADD 12.70
- S50A (p.Ser50Ala), TOPMed rs1270799088, gnomAD rs1270799088
- S50L (p.Ser50Leu), rs73338162, ClinGen CA6646270, ClinVar RCV001686493, 1000Genomes rs73338162, REVEL 0.03, CADD 16.50, Benign, not provided
- S50P (p.Ser50Pro), TOPMed rs1270799088, gnomAD rs1270799088, REVEL 0.11, CADD 20.50
- S50W (p.Ser50Trp), 1000Genomes rs73338162, ESP rs73338162, ExAC rs73338162, TOPMed rs73338162, REVEL 0.08, CADD 22.20, Benign
- S50S (p.Ser50Ser), rs1013269533, gnomAD 12-57230919-G-A, CADD 1.33
- D51E (p.Asp51Glu), TOPMed rs1212618506
- D51H (p.Asp51His), rs755645926, ClinGen CA6646272, ClinVar RCV003351786, ExAC rs755645926, REVEL 0.05, CADD 25.60, Uncertain significance, Inborn genetic diseases
- D51N (p.Asp51Asn), ExAC rs755645926, TOPMed rs755645926, gnomAD rs755645926, Uncertain significance
- S52T (p.Ser52Thr), gnomAD rs1369646344, REVEL 0.04, CADD 19.00
- D53V (p.Asp53Val), gnomAD 12-57230927-A-T, REVEL 0.76, CADD 29.40
- P54S (p.Pro54Ser), ExAC rs763720256, TOPMed rs763720256, gnomAD rs763720256, REVEL 0.39, CADD 26.30
- P54P (p.Pro54Pro), gnomAD 12-57230931-T-G, CADD 12.70
- E55A (p.Glu55Ala), TOPMed rs1326517219
- E55V (p.Glu55Val), TOPMed rs1326517219, REVEL 0.46, CADD 25.30
- M56I (p.Met56Ile), gnomAD rs1162516961, REVEL 0.09, CADD 21.00
- L59F (p.Leu59Phe), gnomAD rs1393127126, REVEL 0.37, CADD 23.70
- L59* (p.Leu59Ter), gnomAD 12-57230945-T-A, CADD 37.00
- L60L (p.Leu60Leu), rs753518474, gnomAD 12-57230949-G-T, CADD 8.85
- Q61* (p.Gln61Ter), gnomAD rs1329038936, CADD 37.00
- Q61H (p.Gln61His), ExAC rs757010542, TOPMed rs757010542, gnomAD rs757010542, REVEL 0.06, CADD 24.30
- Q61Q (p.Gln61Gln), rs757010542, gnomAD 12-57230952-G-A, CADD 12.60
- R62K (p.Arg62Lys), ExAC rs778762177, TOPMed rs778762177, REVEL 0.03, CADD 15.70
- E63G (p.Glu63Gly), Ensembl rs1592681219
- E63E (p.Glu63Glu), rs866950450, gnomAD 12-57230958-G-A, CADD 12.10
- K64E (p.Lys64Glu), Ensembl rs201874066
- K64del (p.Lys64del), rs765524143, gnomAD 12-57230956-GAGA-, CADD 21.60
- K64* (p.Lys64Ter), gnomAD 12-57230959-A-T, CADD 37.00
- K64K (p.Lys64Lys), gnomAD 12-57230961-G-A, CADD 13.10
- D65H (p.Asp65His), ExAC rs745706463, gnomAD rs745706463, REVEL 0.18, CADD 22.70
- R66G (p.Arg66Gly), Ensembl rs972339427
- R66S (p.Arg66Ser), rs1669703332, gnomAD 12-57230965-AG-A, CADD 33.00
- Q67* (p.Gln67Ter), NCI-TCGA TCGA novel, TOPMed rs2037291550, gnomAD rs2037291550, CADD 39.00, Variant assessed as somatic; high impact.
- Q67K (p.Gln67Lys), gnomAD 12-57230968-C-A, REVEL 0.53, CADD 27.60
- C68R (p.Cys68Arg), 1000Genomes rs568519647, ExAC rs568519647, gnomAD rs568519647, REVEL 0.27, CADD 22.80
- C68W (p.Cys68Trp), ESP rs141369249, ExAC rs141369249, gnomAD rs141369249, REVEL 0.28, CADD 23.50
- R69C (p.Arg69Cys), ESP rs373440935, ExAC rs373440935, TOPMed rs373440935, gnomAD rs373440935, REVEL 0.20, CADD 23.90
- R69H (p.Arg69His), ESP rs376369904, ExAC rs376369904, TOPMed rs376369904, gnomAD rs376369904, REVEL 0.11, CADD 23.10
- R69P (p.Arg69Pro), ESP rs376369904, ExAC rs376369904, TOPMed rs376369904, gnomAD rs376369904, REVEL 0.32, CADD 29.10
- R69S (p.Arg69Ser), ESP rs373440935, ExAC rs373440935, TOPMed rs373440935, gnomAD rs373440935, REVEL 0.21, CADD 23.10
- R69G (p.Arg69Gly), gnomAD 12-57230974-C-G, REVEL 0.23, CADD 23.10
- R69R (p.Arg69Arg), gnomAD 12-57230976-T-C, CADD 7.23
- G70A (p.Gly70Ala), TOPMed rs1427117085, gnomAD rs1427117085, REVEL 0.45, CADD 28.20
- G70C (p.Gly70Cys), TOPMed rs1169963526, gnomAD rs1169963526, REVEL 0.50, CADD 32.00
- G70V (p.Gly70Val), TOPMed rs1427117085, gnomAD rs1427117085, REVEL 0.55, CADD 29.40
- L71L (p.Leu71Leu), gnomAD 12-57230982-G-A, CADD 13.90
- E72* (p.Glu72Ter), gnomAD rs1171974393, CADD 37.00
- E72E (p.Glu72Glu), rs1022769651, gnomAD 12-57230985-G-A, CADD 11.80
- L73L (p.Leu73Leu), rs370017022, gnomAD 12-57230988-C-T, CADD 13.90
- I74F (p.Ile74Phe), Ensembl rs2037292972, REVEL 0.64, CADD 29.80
- I74N (p.Ile74Asn), TOPMed rs2037293115, gnomAD rs2037293115, REVEL 0.71, CADD 32.00
- I74T (p.Ile74Thr), TOPMed rs2037293115, gnomAD rs2037293115
- I74L (p.Ile74Leu), gnomAD 12-57230989-A-C, REVEL 0.48, CADD 28.90
- I74I (p.Ile74Ile), rs2037293277, gnomAD 12-57230991-T-C, CADD 11.90
- A75T (p.Ala75Thr), Ensembl rs773986530, REVEL 0.67, CADD 32.00
- A75G (p.Ala75Gly), gnomAD 12-57230993-C-G, REVEL 0.50, CADD 28.10
- S76* (p.Ser76Ter), NCI-TCGA Cosmic COSV1001, cosmic curated COSV10019, Variant assessed as somatic; high impact.
- S76L (p.Ser76Leu), gnomAD 12-57230996-C-T, REVEL 0.64, CADD 25.70
- E77* (p.Glu77Ter), Ensembl rs12319666
- N78Y (p.Asn78Tyr), gnomAD 12-57231481-A-T, REVEL 0.78, CADD 33.00
- F79L (p.Phe79Leu), NCI-TCGA Cosmic COSV6107, cosmic curated COSV61073, Variant assessed as somatic; moderate impact.
- C80G (p.Cys80Gly), Ensembl rs1565769889
- C80Y (p.Cys80Tyr), ExAC rs771179680, gnomAD rs771179680
- C80R (p.Cys80Arg), gnomAD 12-57231487-T-C, REVEL 0.52, CADD 28.80
- S81C (p.Ser81Cys), ExAC rs774894491, gnomAD rs774894491, REVEL 0.66, CADD 31.00
- R82* (p.Arg82Ter), ExAC rs760114958, TOPMed rs760114958, gnomAD rs760114958, CADD 36.00
- R82L (p.Arg82Leu), rs11557163, ClinGen CA385469850, ClinVar RCV002292861, ClinVar RCV004047622, REVEL 0.46, CADD 28.90, Uncertain significance, Inborn genetic diseases; not provided
- R82P (p.Arg82Pro), TOPMed rs11557163, gnomAD rs11557163
- R82Q (p.Arg82Gln), TOPMed rs11557163, gnomAD rs11557163, REVEL 0.22, CADD 24.60
- R82R (p.Arg82Arg), rs760114958, gnomAD 12-57231493-C-A, CADD 16.10
- A84V (p.Ala84Val), ExAC rs554585552, gnomAD rs554585552, REVEL 0.22, CADD 20.50, Uncertain significance, Inborn genetic diseases
- A84A (p.Ala84Ala), gnomAD 12-57231501-G-A, CADD 14.50
- L85P (p.Leu85Pro), gnomAD 12-57231503-T-C, REVEL 0.64, CADD 31.00
- A87T (p.Ala87Thr), rs373156028, cosmic curated COSV61073, ESP rs373156028, ExAC rs373156028, REVEL 0.42, CADD 31.00, Variant assessed as somatic; moderate impact.
- L88V (p.Leu88Val), TOPMed rs1168068668, REVEL 0.06, CADD 17.50
- L88L (p.Leu88Leu), gnomAD 12-57231511-C-T, CADD 12.30
- G89E (p.Gly89Glu), gnomAD rs1488946349, REVEL 0.77, CADD 29.00
- G89G (p.Gly89Gly), gnomAD 12-57231516-G-T, CADD 13.70
- C91R (p.Cys91Arg), TOPMed rs1474967523
- C91Y (p.Cys91Tyr), ExAC rs764829768, gnomAD rs764829768, REVEL 0.65, CADD 32.00
- C91S (p.Cys91Ser), gnomAD 12-57231520-T-A, REVEL 0.55, CADD 28.90
- L92L (p.Leu92Leu), gnomAD 12-57231525-G-A, CADD 14.00
- N93K (p.Asn93Lys), gnomAD rs1261909751, REVEL 0.20, CADD 26.80
Public SHMT2 analysis runs
- SHMT2 analysis run — SHMT2 (702 variants) — completed 2026-08-06