Is CCDC8 p.Arg485Cys (c.1453C>T) pathogenic?

CCDC8 p.Arg485Cys (c.1453C>T) is classified Uncertain significance in CCDC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-30). AlphaMissense: ambiguous (0.4156); Ultra-rare (popmax 0.0236%, nfe).

How common is CCDC8 p.Arg485Cys (c.1453C>T) in the general population?

CCDC8 p.Arg485Cys (c.1453C>T) is ultra-rare (popmax 0.0236%, nfe) (gnomAD).

What do computational predictors say about CCDC8 p.Arg485Cys (c.1453C>T)?

AlphaMissense predicts ambiguous (score 0.4156) — an in-silico prediction, not a clinical call.

CCDC8 p.Arg485Cys

c.1453C>T · rs199580829 · VCV1349039

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4156 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0236%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4156	ambiguous
REVEL	0.278	benign-leaning
SaProt	LLR -7.95	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 5.4	GERP 1.4, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 1,613 bp · p 0.66 · regional, not allelic
Overall
CADD	26.9	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 0.0236% European (non-Finnish) · 279/1,180,028 alleles

Filtering AF 0.0213% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0205%

Overall 0.0194% 313/1,614,210 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0236%	4,229
Middle Eastern	0.0165%	6,062
African / African-American	0.0133%	7,506
Remaining individualsnot grpmax-eligible	0.0128%	7,814
Admixed American	0.0117%	8,574
Finnishnot grpmax-eligible	0.0109%	9,149
East Asian	0.00223%	44,884

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.Arg485Cys
Coding: c.1453C>T
MANE Select: NM_032040
dbSNP: rs199580829
Type: single nucleotide variant
Location: chr19:46411358 (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

Similar variants

CCDC8 p.Arg485His Uncertain significance ★★ ⚠ same residue
CCDC8 p.Arg485Pro Uncertain significance ★★ ⚠ same residue
CCDC8 p.Arg485= Benign/Likely benign ★★ same residue
CCDC8 p.Arg485Gly Uncertain significance ★ ⚠ same residue
CCDC8 p.Ala217Thr Uncertain significance ★★ ⚠ same type
CCDC8 p.Ala293Thr Uncertain significance ★★ ⚠ same type
CCDC8 p.Ala393Val Uncertain significance ★★ ⚠ same type
CCDC8 p.Ala527Val Uncertain significance ★★ ⚠ same type

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-arg485cys (accessed [today's date]).

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