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C2CD6

Chr 2AR

catsper channel auxiliary subunit tau

Also known as: ALS2CR11, C2CD6, SPGF68

NCBI Gene: 151254 UniProt: Q53TS8 OMIM: 619776

The C2CD6 protein is an auxiliary component of the CatSper complex that targets and traffics calcium channels to sperm flagella, essential for sperm hyperactivation and motility during fertilization. Mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis, with onset in childhood or adolescence affecting motor neurons. The gene shows high constraint against loss-of-function variants, indicating it is essential for normal cellular function.

OMIM ResearchSummary from RefSeq, UniProt

An autosomal recessive form of juvenile amyotrophic lateral sclerosis was originally mapped to a region of chromosome 2 that includes this gene. The encoded protein contains a calcium-dependent membrane targeting C2 domain. This domain is often found in proteins that are involved in membrane trafficking and signal transduction. [provided by RefSeq, Jun 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.731 OMIM phenotype

Clinical Summary— C2CD6

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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

1 unique Pathogenic / Likely Pathogenic· 127 VUS of 140 total submissions

Explore recent and relevant literature in Research Assistant →

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.73LOEUF

pLI 0.000

Z-score 3.31

OE 0.56 (0.43–0.73)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.82Z-score

OE missense 0.73 (0.68–0.78)

620 obs / 851.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.56 (0.43–0.73)

0≤0.351.4

Missense OE?0.73 (0.68–0.78)

0≤0.61.4

Synonymous OE?0.76

0≤1.21.6

LoF obs/exp: 36 / 64.7Missense obs/exp: 620 / 851.3Syn Z: 3.27

This gene — mechanism propensity

0.6936th %ile

GOF

0.6833th %ile

LOF

0.3162th %ile

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

DNprediction above median

GOFprediction 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

140 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS127

Likely Benign12

Pathogenic

127

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	0	1	0	1
Likely Pathogenic	0	0	0	0
VUS	1	126	0	127
Likely Benign	0	11	1	12
Benign	0	0	0	0
Total	1	138	1	140

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap C2CD6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →