GDAP1

Chr 8

ganglioside induced differentiation associated protein 1

Also known as: CMT4, CMT4A, CMTRIA

NCBI Gene: 54332 ENSG00000104381 UniProt: Q8TB36

The protein localizes to the mitochondrial outer membrane and functions in a signal transduction pathway during neuronal development. Mutations cause multiple forms of Charcot-Marie-Tooth disease including axonal types 2K, recessive intermediate type A, type 4A, and axonal CMT with vocal cord paresis, inherited in both autosomal dominant and autosomal recessive patterns. The pathogenic mechanism involves gain-of-function effects.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the ganglioside-induced differentiation-associated protein family, which may play a role in a signal transduction pathway during neuronal development. Mutations in this gene have been associated with various forms of Charcot-Marie-Tooth Disease and neuropathy. Two transcript variants encoding different isoforms and a noncoding variant have been identified for this gene. [provided by RefSeq, Feb 2012]

GeneReviews ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.16

Clinical Summary— GDAP1

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Gene-Disease Validity (ClinGen)

Charcot-Marie-Tooth disease · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

106 unique Pathogenic / Likely Pathogenic· 309 VUS of 642 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GDAP1

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.16LOEUF

pLI 0.000

Z-score 1.03

OE 0.74 (0.49–1.16)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.00Z-score

OE missense 0.80 (0.69–0.91)

150 obs / 188.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.74 (0.49–1.16)

0≤0.351.4

Missense OE?0.80 (0.69–0.91)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 14 / 18.8Missense obs/exp: 150 / 188.7Syn Z: -0.51

This gene — mechanism propensity

0.7230th %ile

GOF

0.72top 25%

LOF

0.2582th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, gain-of-function and loss-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports dominant-negative. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median

LOF1 literature citation · 62% of P/LP variants are LoF

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.

Literature Evidence

DNInterestingly, the overexpression of GDAP1, carrying dominant missense mutations, also leads to the fragmentation of the mitochondrial network [11], suggesting that the mutation reported here has a negative dominant effect.1

LOFMitochondrial Dysfunction in a Patient with 8q21.11 Deletion and Charcot-Marie-Tooth Disease Type 2K due to GDAP1 Haploinsufficiency.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

642 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic50

Likely Pathogenic56

VUS309

Likely Benign137

Benign44

Conflicting37

Pathogenic

Likely Pathogenic

309

VUS

137

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	38	9	3	0	50
Likely Pathogenic	28	26	2	0	56
VUS	12	223	74	0	309
Likely Benign	0	0	59	78	137
Benign	0	0	42	2	44
Conflicting	—				37
Total	78	258	180	80	633

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

View in ClinVar →

28 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap GDAP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →