PHGDH

Chr 1

phosphoglycerate dehydrogenase

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

NCBI Gene: 26227 ENSG00000092621 UniProt: O43175

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 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 ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.78

Clinical Summary— PHGDH

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Gene-Disease Validity (ClinGen)

neurometabolic disorder due to serine deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

106 unique Pathogenic / Likely Pathogenic· 314 VUS of 959 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PHGDH

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderatePHGDH-related Neu-Laxova syndromeOTHERAR

definitivePHGDH-related phosphoglycerate dehydrogenase deficiencyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6649th %ile

GOF

0.4777th %ile

LOF

0.3648th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

959 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic49

Likely Pathogenic57

VUS314

Likely Benign473

Benign28

Conflicting28

Pathogenic

Likely Pathogenic

314

VUS

473

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	38	3	8	0	49
Likely Pathogenic	47	9	1	0	57
VUS	3	268	35	8	314
Likely Benign	0	3	206	264	473
Benign	0	0	25	3	28
Conflicting	—				28
Total	88	283	275	275	949

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap PHGDH — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →