PHGDH

Chr 1AR

phosphoglycerate dehydrogenase

Also known as: 3-PGDH, 3PGDH, HEL-S-113, NLS, NLS1, PDG, PGAD, PGD

NCBI Gene: 26227ENSG00000092621UniProt: O43175

This gene encodes the enzyme which is involved in the early steps of L-serine synthesis in animal cells. L-serine is required for D-serine and other amino acid synthesis. The enzyme requires NAD/NADH as a cofactor and forms homotetramers for activity. Mutations in this gene have been found in a family with congenital microcephaly, psychomotor retardation and other symptoms. Multiple alternatively spliced transcript variants have been found, however the full-length nature of most are not known. [provided by RefSeq, Aug 2011]

Primary Disease Associations & Inheritance

Neu-Laxova syndrome 1MIM #256520
AR
Phosphoglycerate dehydrogenase deficiencyMIM #601815
AR
490
ClinVar variants
57
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— PHGDH
🧬
Gene-Disease Validity (ClinGen)
neurometabolic disorder due to serine deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
57 Pathogenic / Likely Pathogenic· 223 VUS of 490 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.
0.78LOEUF
pLI 0.000
Z-score 2.34
OE 0.46 (0.28–0.78)
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.
0.21Z-score
OE missense 0.97 (0.88–1.06)
295 obs / 305.2 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.0.46 (0.28–0.78)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.97 (0.88–1.06)
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.1.06
0≤1.21.6
LoF obs/exp: 10 / 21.8Missense obs/exp: 295 / 305.2Syn Z: -0.57

ClinVar Variant Classifications

490 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic40
Likely Pathogenic17
VUS223
Likely Benign186
Benign20
Conflicting4
40
Pathogenic
17
Likely Pathogenic
223
VUS
186
Likely Benign
20
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
11
4
25
0
40
Likely Pathogenic
11
1
5
0
17
VUS
1
191
24
7
223
Likely Benign
0
0
92
94
186
Benign
0
0
20
0
20
Conflicting
—4
Total23196166101490

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

View in ClinVar →

Protein Context — Lollipop Plot

PHGDH · protein map & ClinVar variants

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

Gene2Phenotype Curations

PHGDH-related Neu-Laxova syndrome

moderate
ARUndeterminedAltered Gene Product Structure
Skin
G2P ↗

PHGDH-related phosphoglycerate dehydrogenase deficiency

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Neu-Laxova syndrome 1

MIM #256520

Molecular basis of disorder known

Autosomal recessive

Phosphoglycerate dehydrogenase deficiency

MIM #601815

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — PHGDH
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Targeting PHGDH reverses the immunosuppressive phenotype of tumor-associated macrophages through α-ketoglutarate and mTORC1 signaling.
Cai Z et al.·Cell Mol Immunol
2024
NRF2 regulates serine biosynthesis in non-small cell lung cancer.
DeNicola GM et al.·Nat Genet
2015
AMPK-HIF-1α signaling enhances glucose-derived de novo serine biosynthesis to promote glioblastoma growth.
Yun HJ et al.·J Exp Clin Cancer Res
2023
The alternative activity of nuclear PHGDH contributes to tumour growth under nutrient stress.
Ma C et al.·Nat Metab
2021
PRMT1 Sustains De Novo Fatty Acid Synthesis by Methylating PHGDH to Drive Chemoresistance in Triple-Negative Breast Cancer.
Yamamoto T et al.·Cancer Res
2024
PHGDH activation fuels glioblastoma progression and radioresistance via serine synthesis pathway.
Liu X et al.·J Exp Clin Cancer Res
2025
Integrative proteogenomic analysis provides molecular insights and clinical significance in gallbladder cancer.
Fu Z et al.·Cancer Cell
2026
Serine biosynthesis as a novel therapeutic target for dilated cardiomyopathy.
Perea-Gil I et al.·Eur Heart J
2022
Harnessing PHGDH Inhibition for Cancer Therapy: Mechanisms, SAR, Computational Aspects, and Clinical Potential.
Islam MM et al.·Arch Pharm (Weinheim)
2025Review
PHGDH at the crossroads: metabolic plasticity, metastatic paradoxes, and therapeutic reconnaissance in cancer.
Hao L et al.·J Biomed Sci
2026Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
RNA-binding activity of PHGDH drives amyloid-beta production in a human brain organoid model of sporadic Alzheimer's disease.
Chen J et al.·Proc Natl Acad Sci U S A
2026🔓 Open AccessFunctional
Screening of Natural Inhibitors from Pleurotus ostreatus against PHGDH for Enhancing Antiviral Innate Immunity through Mendelian Randomization, Machine Learning, Molecular Docking, Molecular Dynamics Simulation, and Binding Free Energy Calculation.
Xu S et al.·ACS Omega
2026🔓 Open Access
PHGDH knockdown activates autophagic flux to suppress migration and invasion of gastric cancer cells.
Li S et al.·Transl Cancer Res
2026🔓 Open Access
tRF-Gly-CCC-012 enhances malignant process in pancreatic cancer via the HNRNPC/PHGDH axis.
Li X et al.·Biochem Pharmacol
2026
Understanding and Managing Infantile PHGDH Deficiency: A Case Report.
Nilay M et al.·Neurol India
2026Case report
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