CCDC127

Chr 5

coiled-coil domain containing 127

NCBI Gene: 133957 ENSG00000164366 UniProt: Q96BQ5 OMIM: 621138

The protein regulates lipid droplet homeostasis and may be involved in adipocyte differentiation within mitochondria. Mutations cause autosomal recessive disorders affecting multiple organ systems. This gene is not highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

Located in mitochondrion. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.07

Clinical Summary— CCDC127

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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

42 VUS of 50 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?

1.07LOEUF

pLI 0.000

Z-score 1.40

OE 0.57 (0.32–1.07)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.61Z-score

OE missense 0.86 (0.75–0.99)

131 obs / 152.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.57 (0.32–1.07)

0≤0.351.4

Missense OE?0.86 (0.75–0.99)

0≤0.61.4

Synonymous OE?1.24

0≤1.21.6

LoF obs/exp: 7 / 12.3Missense obs/exp: 131 / 152.2Syn Z: -1.42

This gene — mechanism propensity

0.6841th %ile

GOF

0.81top 10%

LOF

0.2777th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

50 submitted variants in ClinVar

ClinVar

Classification Summary

VUS42

Likely Benign3

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	42	42
Likely Benign	3	3
Benign	0	0
Total	45	45

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

View in ClinVar →

132 pathogenic / likely-pathogenic (of 165) ClinVar copy-number / structural variants overlap CCDC127 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →