IGHMBP2

Chr 11AR

immunoglobulin mu DNA binding protein 2

Also known as: CATF1, CMT2S, HCSA, HMN6, HMNR1, SMARD1, SMUBP2, ZFAND7

NCBI Gene: 3508ENSG00000132740UniProt: P38935

This gene encodes a helicase superfamily member that binds a specific DNA sequence from the immunoglobulin mu chain switch region. Mutations in this gene lead to spinal muscle atrophy with respiratory distress type 1. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Charcot-Marie-Tooth disease, axonal, type 2SMIM #616155
AR
Neuronopathy, distal hereditary motor, autosomal recessive 1MIM #604320
AR
487
ClinVar variants
66
Pathogenic / LP
0.00
pLI score
2
Active trials
Clinical Summary— IGHMBP2
🧬
Gene-Disease Validity (ClinGen)
hereditary peripheral neuropathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
66 Pathogenic / Likely Pathogenic· 120 VUS of 487 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.95LOEUF
pLI 0.000
Z-score 1.81
OE 0.71 (0.53–0.95)
Tolerant

Typical tolerance to LoF variation

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.
0.18Z-score
OE missense 0.98 (0.91–1.05)
580 obs / 592.1 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.0.71 (0.53–0.95)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.98 (0.91–1.05)
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.1.11
0≤1.21.6
LoF obs/exp: 31 / 43.9Missense obs/exp: 580 / 592.1Syn Z: -1.40

ClinVar Variant Classifications

487 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic37
Likely Pathogenic29
VUS120
Likely Benign297
Benign2
Conflicting2
37
Pathogenic
29
Likely Pathogenic
120
VUS
297
Likely Benign
2
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
25
0
12
0
37
Likely Pathogenic
14
7
8
0
29
VUS
0
108
10
2
120
Likely Benign
0
3
119
175
297
Benign
0
0
1
1
2
Conflicting
—2
Total39118150178487

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

View in ClinVar →

Protein Context — Lollipop Plot

IGHMBP2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

IGHMBP2-related spinal muscular atrophy with respiratory distress

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Charcot-Marie-Tooth disease, axonal, type 2S

MIM #616155

Molecular basis of disorder known

Autosomal recessive

Neuronopathy, distal hereditary motor, autosomal recessive 1

MIM #604320

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — IGHMBP2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Distal hereditary motor neuropathies.
Tazir M et al.·Rev Neurol (Paris)
2024Review
Models for IGHMBP2-associated diseases: an overview and a roadmap for the future.
Rzepnikowska W et al.·Neuromuscul Disord
2021Review
The molecular mechanisms that underlie IGHMBP2-related diseases.
Rzepnikowska W et al.·Neuropathol Appl Neurobiol
2024Review
[Hereditary peripheral neuropathies].
Vallat JM et al.·Presse Med
2009Review
Clinical and genetic features of Charcot-Marie-Tooth disease patients with IGHMBP2 mutations.
Lei L et al.·Neuromuscul Disord
2022Cohort
IGHMBP2 deletion suppresses translation and activates the integrated stress response.
Park J et al.·Life Sci Alliance
2024
Clinical and Genetic Landscape of IGHMBP2 -Related Disorders: From Novel Variants to Phenotypic Insights.
Tkemaladze T et al.·Am J Med Genet A
2025Case report
Noncoding variants are a rare cause of recessive developmental disorders in trans with coding variants.
Lord J et al.·Genet Med
2024
IGHMBP2-related clinical and genetic features in a cohort of Chinese Charcot-Marie-Tooth disease type 2 patients.
Liu L et al.·Neuromuscul Disord
2017Cohort
Novel biallelic nonsense mutation in IGHMBP2 gene linked to neuropathy (CMT2S): A comprehensive clinical, genetic and bioinformatic analysis of a Turkish patient with literature review.
Yavas C et al.·Brain Dev
2025Review
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
Charcot Marie Tooth Disease (CMT)Neuromuscular Diseases (NMD)

Treatment of Charcot-Marie-Tooth Disease, Axonal, Type 2S (CMT2S) in an Individual Patient

ACTIVE NOT RECRUITING
NCT07223632Phase PHASE1, PHASE2Vanda PharmaceuticalsStarted 2025-05-13
VCA-894A
SMARD1CMT2S

Gene Therapy for IGHMBP2-Related Diseases

ENROLLING BY INVITATION
NCT05152823Phase PHASE1, PHASE2Megan WaldropStarted 2021-11-04
Gene Therapy

External Resources

Links to major genomics databases and tools