NDRG1

Chr 8AR

N-myc downstream regulated 1

Also known as: CAP43, CMT4D, DRG-1, DRG1, GC4, HMSNL, NDR1, NMSL

NCBI Gene: 10397 ENSG00000104419 UniProt: Q92597 OMIM: 605262

The protein encoded by NDRG1 is a cytoplasmic stress-responsive protein that regulates cell growth and differentiation, maintains peripheral nerve myelin sheaths in Schwann cells, and is necessary for p53-mediated caspase activation and apoptosis. Autosomal recessive mutations cause Charcot-Marie-Tooth disease type 4D through a predicted gain-of-function mechanism. The protein functions in cell trafficking, vesicular recycling, and microtubule dynamics, with disruption of these processes leading to peripheral neuropathy.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene is a member of the N-myc downregulated gene family which belongs to the alpha/beta hydrolase superfamily. The protein encoded by this gene is a cytoplasmic protein involved in stress responses, hormone responses, cell growth, and differentiation. The encoded protein is necessary for p53-mediated caspase activation and apoptosis. Mutations in this gene are a cause of Charcot-Marie-Tooth disease type 4D, and expression of this gene may be a prognostic indicator for several types of cancer. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.581 OMIM phenotype

Clinical Summary— NDRG1

⚡

Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — NDRG1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.58LOEUF

pLI 0.011

Z-score 3.14

OE 0.32 (0.19–0.58)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.65Z-score

OE missense 0.89 (0.79–0.99)

226 obs / 255.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.32 (0.19–0.58)

0≤0.351.4

Missense OE?0.89 (0.79–0.99)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 8 / 24.9Missense obs/exp: 226 / 255.3Syn Z: -0.66

This gene — mechanism propensity

0.6358th %ile

GOF

0.6638th %ile

LOF

0.3842th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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