SH3TC2

Chr 5ARAD

SH3 domain and tetratricopeptide repeats 2

Also known as: CMT4C, MNMN

NCBI Gene: 79628ENSG00000169247UniProt: Q8TF17

This gene encodes a protein with two N-terminal Src homology 3 (SH3) domains and 10 tetratricopeptide repeat (TPR) motifs, and is a member of a small gene family. The gene product has been proposed to be an adapter or docking molecule. Mutations in this gene result in autosomal recessive Charcot-Marie-Tooth disease type 4C, a childhood-onset neurodegenerative disease characterized by demyelination of motor and sensory neurons. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Charcot-Marie-Tooth disease, type 4CMIM #601596
AR
Mononeuropathy of the median nerve, mildMIM #613353
AD
0
ClinVar variants
0
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— SH3TC2
🧬
Gene-Disease Validity (ClinGen)
obsolete autosomal recessive hereditary demyelinating motor and sensory 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.
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

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.
0.81LOEUF
pLI 0.000
Z-score 2.67
OE 0.61 (0.46–0.81)
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.
-0.71Z-score
OE missense 1.08 (1.01–1.15)
721 obs / 669.1 exp
Tolerant

Tolerant to missense variation

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.0.61 (0.46–0.81)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.08 (1.01–1.15)
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: 33 / 54.3Missense obs/exp: 721 / 669.1Syn Z: -1.40

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

SH3TC2 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Charcot-Marie-Tooth disease, type 4C

MIM #601596

Molecular basis of disorder known

Autosomal recessive

Mononeuropathy of the median nerve, mild

MIM #613353

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — SH3TC2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical spectrum and frequency of Charcot-Marie-Tooth disease in Italy: Data from the National CMT Registry.
Pisciotta C et al.·Eur J Neurol
2023
Clinical and mutational spectrum of Japanese patients with recessive variants in SH3TC2.
Yuan JH et al.·J Hum Genet
2018Cohort
Two novel SH3TC2 mutations predispose to Charcot-Marie-Tooth disease type 4C by mistargeting away from TFRC.
Li P et al.·Cell Signal
2025
Evaluation of Pathogenicity and Causativity of Variants in the MPZ and SH3TC2 Genes in a Family Case of Hereditary Peripheral Neuropathy.
Shchagina O et al.·Int J Mol Sci
2023
Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy.
Jaubert P et al.·Eur J Neurol
2025Cohort
Electrophysiological findings in SH3TC2 neuropathy mimicking inflammatory neuropathies.
Frezatti RSS et al.·J Neurol Neurosurg Psychiatry
2025
Clinical, in silico, and experimental evidence for pathogenicity of two novel splice site mutations in the SH3TC2 gene.
Laššuthová P et al.·J Neurogenet
2012
Implication of the SH3TC2 gene in Charcot-Marie-Tooth disease associated with deafness and/or scoliosis: Illustration with four new pathogenic variants.
Lerat J et al.·J Neurol Sci
2019
Current profile of Charcot-Marie-Tooth disease in Africa: A systematic review.
Yalcouyé A et al.·J Peripher Nerv Syst
2022Review
Gene replacement therapy in a model of Charcot-Marie-Tooth 4C neuropathy.
Schiza N et al.·Brain
2019Functional
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.

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External Resources

Links to major genomics databases and tools