CCDC88A

Chr 2AR

coiled-coil and HOOK domain protein 88A

Also known as: APE, GIRDIN, GIV, GRDN, HkRP1, KIAA1212, PEHO, PEHOL

NCBI Gene: 55704 ENSG00000115355 UniProt: Q3V6T2 OMIM: 609736

The protein functions as a bifunctional modulator of G proteins, acting as both a guanine nucleotide exchange factor for G(i) alpha subunits and a dissociation inhibitor for G(s) alpha subunits, while also serving as an actin-binding protein essential for cytoskeleton integrity, cell migration, and ciliogenesis. Autosomal recessive mutations cause PEHO syndrome-like disorder, a severe early-onset neurodevelopmental condition. The gene is highly constrained against loss-of-function variants (pLI ~1.0, LOEUF 0.13), indicating strong evolutionary pressure to maintain protein function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the Girdin family of coiled-coil domain containing proteins. The encoded protein is an actin-binding protein that is activated by the serine/threonine kinase Akt and plays a role in cytoskeleton remodeling and cell migration. The encoded protein also enhances Akt signaling by mediating phosphoinositide 3-kinase (PI3K)-dependent activation of Akt by growth factor receptor tyrosine kinases and G protein-coupled receptors. Increased expression of this gene and phosphorylation of the encoded protein may play a role in cancer metastasis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.131 OMIM phenotype

Clinical Summary— CCDC88A

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.13LOEUF

pLI 1.000

Z-score 8.66

OE 0.07 (0.04–0.13)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

2.35Z-score

OE missense 0.78 (0.73–0.83)

678 obs / 873.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.07 (0.04–0.13)

0≤0.351.4

Missense OE?0.78 (0.73–0.83)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 7 / 100.8Missense obs/exp: 678 / 873.4Syn Z: -0.18

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateCCDC88A-related PEHO-like syndrome with neuronal migration disorder, seizures and microcephalyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.4189th %ile

GOF

0.4481th %ile

LOF

0.71top 10%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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