DHFR2

Chr 3

dihydrofolate reductase 2

Also known as: DHFRL1, DHFRP4

NCBI Gene: 200895 ENSG00000178700 UniProt: Q86XF0 OMIM: 616588

The protein is a key enzyme in mitochondrial folate metabolism that catalyzes dihydrofolate reduction and contributes to thymidylate biosynthesis, preventing uracil accumulation in mitochondrial DNA. Mutations cause autosomal recessive mitochondrial DNA depletion syndrome, which typically presents in infancy with severe neurological deterioration, developmental delays, and multi-organ dysfunction. The gene shows moderate tolerance to loss-of-function variants, consistent with the recessive inheritance pattern observed in affected patients.

OMIM ResearchSummary from RefSeq, UniProt

Enables dihydrofolate reductase activity and mRNA binding activity. Involved in tetrahydrofolate metabolic process and thymidine biosynthetic process. Located in mitochondrial inner membrane and mitochondrial matrix. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.44

Clinical Summary— DHFR2

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Population Constraint (gnomAD)

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

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ClinVar Variants

4 VUS of 9 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.44LOEUF

pLI 0.225

Z-score 1.10

OE 0.32 (0.11–1.44)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.60Z-score

OE missense 0.83 (0.69–1.00)

81 obs / 97.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.32 (0.11–1.44)

0≤0.351.4

Missense OE?0.83 (0.69–1.00)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 1 / 3.1Missense obs/exp: 81 / 97.6Syn Z: -0.83

This gene — mechanism propensity

0.6936th %ile

GOF

0.5563th %ile

LOF

0.2485th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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.

ClinVar Variant Classifications

9 submitted variants in ClinVar

ClinVar

Classification Summary

VUS4

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	2	2	4
Likely Benign	0	0	0
Benign	0	0	0
Total	2	2	4

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap DHFR2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →