GDAP1

Chr 8ADAR

ganglioside induced differentiation associated protein 1

ENSG00000104381 UniProt: Q8TB36 OMIM: 606598

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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

MultiplemechanismAD/ARLOEUF 1.164 OMIM phenotypes

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

76 unique Pathogenic / Likely Pathogenic· 179 VUS of 371 total submissions

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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 OE0.74 (0.49–1.16)

0≤0.351.4

Missense OE0.80 (0.69–0.91)

0≤0.61.4

Synonymous OE1.08

0≤1.21.6

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

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 · 55% 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.PMID:19089472

LOFMitochondrial Dysfunction in a Patient with 8q21.11 Deletion and Charcot-Marie-Tooth Disease Type 2K due to GDAP1 Haploinsufficiency.PMID:26648837

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