NFS1

Chr 20

NFS1 cysteine desulfurase

Also known as: COXPD52, HUSSY-08, IscS, NIFS

NCBI Gene: 9054ENSG00000244005UniProt: Q9Y697

Iron-sulfur clusters are required for the function of many cellular enzymes. The proteins encoded by this gene supply inorganic sulfur to these clusters by removing the sulfur from cysteine, creating alanine in the process. This gene uses alternate in-frame translation initiation sites to generate mitochondrial forms and cytoplasmic/nuclear forms. Selection of the alternative initiation sites is determined by the cytosolic pH. The encoded proteins belong to the class-V family of pyridoxal phosphate-dependent aminotransferases. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2010]

Primary Disease Associations & Inheritance

UniProtCombined oxidative phosphorylation deficiency 52
191
ClinVar variants
14
Pathogenic / LP
0.06
pLI score
0
Active trials
Clinical Summary— NFS1
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.28) despite low pLI — interpret in context.
📋
ClinVar Variants
14 Pathogenic / Likely Pathogenic· 76 VUS of 191 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.53LOEUF
pLI 0.055
Z-score 3.32
OE 0.28 (0.16–0.53)
Moderately constrained

More LoF-intolerant than ~75% of genes

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.
1.41Z-score
OE missense 0.75 (0.67–0.85)
196 obs / 260.0 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.0.28 (0.16–0.53)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.75 (0.67–0.85)
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.0.97
0≤1.21.6
LoF obs/exp: 7 / 24.8Missense obs/exp: 196 / 260.0Syn Z: 0.23

ClinVar Variant Classifications

191 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12
Likely Pathogenic2
VUS76
Likely Benign75
Benign24
Conflicting2
12
Pathogenic
2
Likely Pathogenic
76
VUS
75
Likely Benign
24
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
12
0
12
Likely Pathogenic
0
0
2
0
2
VUS
2
72
2
0
76
Likely Benign
0
4
47
24
75
Benign
0
0
23
1
24
Conflicting
—2
Total2768625191

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

View in ClinVar →

Protein Context — Lollipop Plot

NFS1 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Impaired Iron-Sulfur Cluster Synthesis Induces Mitochondrial PARthanatos in Diabetic Cardiomyopathy.
Wang M et al.·Adv Sci (Weinh)
2025
Hippo pathway activation mediates cardiomyocyte ferroptosis to promote dilated cardiomyopathy through downregulating NFS1.
She G et al.·Redox Biol
2025
NFS1 Plays a Critical Role in Regulating Ferroptosis Homeostasis.
Sun S et al.·Biomolecules
2025Review
Mutations in mitochondrial ferredoxin FDX2 suppress frataxin deficiency.
Meisel JD et al.·Nature
2026
Identification and characterization of novel ferroptosis-related genes in acute myocardial infarction.
Zhou Q et al.·Hum Genomics
2024
Structure of the Human ACP-ISD11 Heterodimer.
Herrera MG et al.·Biochemistry
2019
Integration of epigenomic and transcriptomic profiling uncovers EZH2 target genes linked to cysteine metabolism in hepatocellular carcinoma.
Lee J et al.·Cell Death Dis
2024
A Bimetallic Polymerization Network for Effective Increase in Labile Iron Pool and Robust Activation of cGAS/STING Induces Ferroptosis-Based Tumor Immunotherapy.
Wang Z et al.·Small
2024
Frataxin Traps Low Abundance Quaternary Structure to Stimulate Human Fe-S Cluster Biosynthesis.
Cory SA et al.·Biochemistry
2025
Expanding the phenotypic and molecular spectrum of NFS1-related disorders that cause functional deficiencies in mitochondrial and cytosolic iron-sulfur cluster containing enzymes.
Yang JH et al.·Hum Mutat
2022Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
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