SHMT1

Chr 17

serine hydroxymethyltransferase 1

Also known as: CSHMT, SHMT, hcSHMT

NCBI Gene: 6470ENSG00000176974UniProt: P34896

This gene encodes the cytosolic form of serine hydroxymethyltransferase, a pyridoxal phosphate-containing enzyme that catalyzes the reversible conversion of serine and tetrahydrofolate to glycine and 5,10-methylene tetrahydrofolate. This reaction provides one-carbon units for synthesis of methionine, thymidylate, and purines in the cytoplasm. This gene is located within the Smith-Magenis syndrome region on chromosome 17. A pseudogene of this gene is located on the short arm of chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

192
ClinVar variants
113
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— SHMT1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
113 Pathogenic / Likely Pathogenic· 61 VUS of 192 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.
1.36LOEUF
pLI 0.000
Z-score 0.20
OE 0.95 (0.68–1.36)
Tolerant

Highly tolerant — LoF variants common in population

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.
0.35Z-score
OE missense 0.94 (0.85–1.04)
259 obs / 275.5 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.0.95 (0.68–1.36)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.94 (0.85–1.04)
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: 22 / 23.1Missense obs/exp: 259 / 275.5Syn Z: -0.66

ClinVar Variant Classifications

192 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic113
VUS61
Likely Benign9
Benign9
113
Pathogenic
61
VUS
9
Likely Benign
9
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
113
0
113
Likely Pathogenic
0
0
0
0
0
VUS
0
58
3
0
61
Likely Benign
0
5
3
1
9
Benign
0
3
3
3
9
Total0661224192

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

View in ClinVar →

Protein Context — Lollipop Plot

SHMT1 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical significance of SHMT1 rs1979277 polymorphism in Asian solid tumors: evidence from a meta-analysis.
Zhao TT et al.·Genet Mol Res
2015Meta-analysis
HOXD8 suppresses renal cell carcinoma growth by upregulating SHMT1 expression.
Yang Y et al.·Cancer Sci
2023
A SHMT1 variant decreases the risk of nonsyndromic cleft lip with or without cleft palate in Chile.
Salamanca C et al.·Oral Dis
2020
SHMT1, an amino acid metabolism-related gene, is an independent prognostic biomarker in laryngeal squamous cell carcinoma.
Lin D et al.·BMC Cancer
2025
SHMT as a Potential Therapeutic Target for Renal Cell Carcinoma.
Situ Y et al.·Front Biosci (Landmark Ed)
2023
Proteogenomic Characterization Reveals Metabolic Vulnerabilities and Aberrant Phosphorylation in Colorectal Metastasis to Liver.
Zhao W et al.·Adv Sci (Weinh)
2026
SHMT1 inhibits the metastasis of HCC by repressing NOX1-mediated ROS production.
Dou C et al.·J Exp Clin Cancer Res
2019
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
Association of SHMT1, MAZ, ERG, and L3MBTL3 Gene Polymorphisms with Susceptibility to Multiple Sclerosis.
Nazari Mehrabani SZ et al.·Biochem Genet
2019
Integrative bioinformatics approach identifies novel drug targets for hyperaldosteronism, with a focus on SHMT1 as a promising therapeutic candidate.
Jia M et al.·Sci Rep
2025
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