Is CCDC8 p.Arg485Pro (c.1454G>C) pathogenic?

CCDC8 p.Arg485Pro (c.1454G>C) is classified Uncertain significance in CCDC8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-30). AlphaMissense: ambiguous (0.5576); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with CCDC8 p.Arg485Pro (c.1454G>C)?

CCDC8 p.Arg485Pro (c.1454G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CCDC8 p.Arg485Pro (c.1454G>C) in the general population?

CCDC8 p.Arg485Pro (c.1454G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CCDC8 p.Arg485Pro (c.1454G>C)?

AlphaMissense predicts ambiguous (score 0.5576) — an in-silico prediction, not a clinical call.

CCDC8 p.Arg485Pro

c.1454G>C · rs747693764 · VCV1930149

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5576 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5576	ambiguous
REVEL	0.22	benign-leaning
SaProt	LLR -6.57	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.4, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 1,613 bp · p 0.66 · regional, not allelic
Overall
CADD	25.3	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 0.00167% Admixed American · 1/60,020 alleles

Overall 6.84e-05% 1/1,461,890 alleles · very rare

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.Arg485Pro
Coding: c.1454G>C
MANE Select: NM_032040
dbSNP: rs747693764
Type: single nucleotide variant
Location: chr19:46411357 (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.Arg485His Uncertain significance ★★ ⚠ same residue
CCDC8 p.Arg485= Benign/Likely benign ★★ same residue
CCDC8 p.Arg485Cys Uncertain significance ★ ⚠ same residue
CCDC8 p.Arg485Gly Uncertain significance ★ ⚠ same residue
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

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-arg485pro (accessed [today's date]).

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