PHGDH

Chr 1AR

phosphoglycerate dehydrogenase

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

NCBI Gene: 26227 ENSG00000092621 UniProt: O43175 OMIM: 606879

The enzyme catalyzes the first step of L-serine biosynthesis by oxidizing 3-phospho-D-glycerate to 3-phosphonooxypyruvate, requiring NAD/NADH as a cofactor. Biallelic mutations cause autosomal recessive phosphoglycerate dehydrogenase deficiency and Neu-Laxova syndrome 1, both presenting with severe congenital microcephaly and developmental delay. The gene shows tolerance to loss-of-function variants (LOEUF 0.778), suggesting complete loss of enzyme function may be required for disease manifestation.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Neu-Laxova syndrome 1MIM #256520

Phosphoglycerate dehydrogenase deficiencyMIM #601815

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · neurometabolic disorder due to serine deficiency · AR · ClinGen 2020

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

197

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.78

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — PHGDH

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.78LOEUF

pLI 0.000

Z-score 2.34

OE 0.46 (0.28–0.78)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.21Z-score

OE missense 0.97 (0.88–1.06)

295 obs / 305.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.46 (0.28–0.78)

0≤0.351.4

Missense OE?0.97 (0.88–1.06)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 10 / 21.8Missense obs/exp: 295 / 305.2Syn Z: -0.57

Background carrier burden — how many people carry a rare variant somewhere in PHGDH?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 67

733 rare PASS variants

Rare truncating (LoF)

1 in 1,600

119 rare PASS variants

Rare synonymous (reference)

1 in 150

222 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PHGDH. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 86	1 in 1,700
South Asian	~43k	1 in 77	1 in 1,300
Remaining (unassigned)	~30k	1 in 61	1 in 3,000
European (Finnish)	~27k	1 in 210	none seen
Admixed American	~22k	1 in 78	1 in 1,900
African / African American	~21k	1 in 83	1 in 1,300
East Asian	~20k	1 in 74	1 in 1,100
Ashkenazi Jewish	~13k	1 in 130	≈ 1 in 4,400
Middle Eastern	~2,884	1 in 100	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 11 of 12 coding exons well covered in gnomAD exomes; exon 5 marginal. Genomes: all 12.? see exons ↓