SH3TC2

Chr 5ARAD

SH3 domain and tetratricopeptide repeats 2

Also known as: CMT4C, MNMN

NCBI Gene: 79628 ENSG00000169247 UniProt: Q8TF17 OMIM: 608206

This gene encodes an adapter protein containing two SH3 domains and 10 tetratricopeptide repeat motifs that localizes to the cell membrane. Mutations cause autosomal recessive Charcot-Marie-Tooth disease type 4C, a childhood-onset neurodegenerative disorder characterized by demyelination of motor and sensory neurons, and can also cause mild median nerve mononeuropathy with autosomal dominant inheritance. The pathogenic mechanism appears to involve gain-of-function effects.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Charcot-Marie-Tooth disease, type 4CMIM #601596

Mononeuropathy of the median nerve, mildMIM #613353

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Charcot-Marie-Tooth disease type 4C · AR · ClinGen 2026

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.81

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — SH3TC2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.81LOEUF

pLI 0.000

Z-score 2.67

OE 0.61 (0.46–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.71Z-score

OE missense 1.08 (1.01–1.15)

721 obs / 669.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.61 (0.46–0.81)

0≤0.351.4

Missense OE?1.08 (1.01–1.15)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 33 / 54.3Missense obs/exp: 721 / 669.1Syn Z: -1.40

Background carrier burden — how many people carry a rare variant somewhere in SH3TC2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 29

1,640 rare PASS variants

Rare truncating (LoF)

1 in 770

205 rare PASS variants

Rare synonymous (reference)

1 in 57

679 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SH3TC2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 40	1 in 790
South Asian	~43k	1 in 29	1 in 350
Remaining (unassigned)	~30k	1 in 24	1 in 380
European (Finnish)	~27k	1 in 120	1 in 540
Admixed American	~22k	1 in 32	1 in 940
African / African American	~21k	1 in 28	1 in 520
East Asian	~20k	1 in 32	1 in 510
Ashkenazi Jewish	~13k	1 in 130	≈ 1 in 4,400
Middle Eastern	~2,884	1 in 27	≈ 1 in 960

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 14 of 17 coding exons well covered in gnomAD exomes; exons 2, 4, 7 marginal. Genomes: all 17.? see exons ↓