Is CCDC8 p.Arg18Ser (c.54G>T) pathogenic?

CCDC8 p.Arg18Ser (c.54G>T) is classified Uncertain significance in CCDC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-24). AlphaMissense: likely pathogenic (0.7734); Ultra-rare (popmax 0.0187%, sas); Associated with Inborn genetic diseases.

What condition is associated with CCDC8 p.Arg18Ser (c.54G>T)?

CCDC8 p.Arg18Ser (c.54G>T) is associated with Inborn genetic diseases (ClinVar).

How common is CCDC8 p.Arg18Ser (c.54G>T) in the general population?

CCDC8 p.Arg18Ser (c.54G>T) is ultra-rare (popmax 0.0187%, sas) (gnomAD).

What do computational predictors say about CCDC8 p.Arg18Ser (c.54G>T)?

AlphaMissense predicts likely pathogenic (score 0.7734) — an in-silico prediction, not a clinical call.

CCDC8 p.Arg18Ser

c.54G>T · VCV4606940

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7734 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7734	likely pathogenic · top 8% in CCDC8
REVEL	0.092	moderately benign-leaning
SaProt	LLR -7.82	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.18	GERP -1.1, phastCons 0.46
Regional constraint	o/e 1.02	unconstrained · MANE · 1,613 bp · p 0.66 · regional, not allelic
Overall
CADD	16.72	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% South Asian · 17/91,078 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00976%

Overall 0.00123% 18/1,461,730 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0187%	5,358
Remaining individualsnot grpmax-eligible	0.0016%	62,508

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CCDC8
Protein: p.Arg18Ser
Coding: c.54G>T
MANE Select: NM_032040
Type: single nucleotide variant
Location: chr19:46412757 (GRCh38)
Gene constraint: LOEUF 1.796 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 46.83 · 1 PDB

Full CCDC8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CCDC8 p.Ala217Thr Uncertain significance ★★ ⚠ same condition
CCDC8 p.Ala293Thr Uncertain significance ★★ ⚠ same condition
CCDC8 p.Ala393Val Uncertain significance ★★ ⚠ same condition
CCDC8 p.Ala527Val Uncertain significance ★★ ⚠ same condition
CCDC8 p.Arg15Gln Uncertain significance ★★ ⚠ same condition
CCDC8 p.Arg225Gly Uncertain significance ★★ ⚠ same condition
CCDC8 p.Arg277His Uncertain significance ★★ ⚠ same condition
CCDC8 p.Arg277Ser Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ccdc8-p-arg18ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown