SHMT2

Chr 12AR

serine hydroxymethyltransferase 2

Also known as: GLYA, HEL-S-51e, NEDCASB, SHMT, mSHMT

NCBI Gene: 6472ENSG00000182199UniProt: P34897

This gene encodes the mitochondrial form of a pyridoxal phosphate-dependent enzyme that catalyzes the reversible reaction of serine and tetrahydrofolate to glycine and 5,10-methylene tetrahydrofolate. The encoded product is primarily responsible for glycine synthesis. The activity of the encoded protein has been suggested to be the primary source of intracellular glycine. The gene which encodes the cytosolic form of this enzyme is located on chromosome 17. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalitiesMIM #619121
AR
101
ClinVar variants
12
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— SHMT2
🧬
Gene-Disease Validity (ClinGen)
neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities · ARLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
12 Pathogenic / Likely Pathogenic· 71 VUS of 101 total submissions

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.
0.85LOEUF
pLI 0.000
Z-score 2.16
OE 0.56 (0.38–0.85)
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.
1.52Z-score
OE missense 0.76 (0.68–0.84)
234 obs / 309.4 exp
Tolerant

Mild missense constraint

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.0.56 (0.38–0.85)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.76 (0.68–0.84)
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.1.08
0≤1.21.6
LoF obs/exp: 16 / 28.4Missense obs/exp: 234 / 309.4Syn Z: -0.68

ClinVar Variant Classifications

101 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7
Likely Pathogenic5
VUS71
Likely Benign9
Benign8
Conflicting1
7
Pathogenic
5
Likely Pathogenic
71
VUS
9
Likely Benign
8
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
7
0
7
Likely Pathogenic
0
3
2
0
5
VUS
1
64
6
0
71
Likely Benign
1
3
0
5
9
Benign
0
1
5
2
8
Conflicting
—1
Total271207101

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

View in ClinVar →

Protein Context — Lollipop Plot

SHMT2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SHMT2-related neurodevelopmental syndrome

strong
ARUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities

MIM #619121

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Metabolic phenotype of bladder cancer.
Massari F et al.·Cancer Treat Rev
2016Review
NRF2 regulates serine biosynthesis in non-small cell lung cancer.
DeNicola GM et al.·Nat Genet
2015
Unraveling the role of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer by multi-omics analyses.
Lee SE et al.·Nat Commun
2024
SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma.
Wilke AC et al.·Blood
2022
TFE3 and HIF1α regulates the expression of SHMT2 isoforms via alternative promoter utilization in ovarian cancer cells.
Wang SQ et al.·Cell Death Dis
2025
Evaluating the clinical significance of SHMT2 and its co-expressed gene in human kidney cancer.
Wang H et al.·Biol Res
2020
The m(6)A writer RBM15 drives the growth of triple-negative breast cancer cells through the stimulation of serine and glycine metabolism.
Park SH et al.·Exp Mol Med
2024
Serine hydroxymethyltransferase 2: a novel target for human cancer therapy.
Xie M et al.·Invest New Drugs
2021Review
Hypoxia-induced SHMT2 protein lactylation facilitates glycolysis and stemness of esophageal cancer cells.
Qiao Z et al.·Mol Cell Biochem
2024
SHMT as a Potential Therapeutic Target for Renal Cell Carcinoma.
Situ Y et al.·Front Biosci (Landmark Ed)
2023
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