Is CCDC8 p.Arg433Trp (c.1297C>T) pathogenic?

CCDC8 p.Arg433Trp (c.1297C>T) is classified Uncertain significance in CCDC8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-02-04). AlphaMissense: likely benign (0.1285); Very rare (popmax 0.00881%, sas); Associated with Inborn genetic diseases.

What condition is associated with CCDC8 p.Arg433Trp (c.1297C>T)?

CCDC8 p.Arg433Trp (c.1297C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CCDC8 p.Arg433Trp (c.1297C>T) in the general population?

CCDC8 p.Arg433Trp (c.1297C>T) is very rare (popmax 0.00881%, sas) (gnomAD).

What do computational predictors say about CCDC8 p.Arg433Trp (c.1297C>T)?

AlphaMissense predicts likely benign (score 0.1285) — an in-silico prediction, not a clinical call.

CCDC8 p.Arg433Trp

c.1297C>T · rs746276818 · VCV2063506

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1285 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00881%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1285	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -9.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.4	GERP -2
Regional constraint	o/e 1.02	unconstrained · MANE · 1,613 bp · p 0.66 · regional, not allelic
Overall
CADD	12.14	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00881% South Asian · 8/90,788 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00313%

Overall 0.00404% 65/1,607,312 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00881%	11,348
Admixed American	0.00673%	14,860
Remaining individualsnot grpmax-eligible	0.00642%	15,579
European (non-Finnish)	0.00391%	25,599
African / African-American	0.00274%	36,450
Finnishnot grpmax-eligible	0.00158%	63,474

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.Arg433Trp
Coding: c.1297C>T
MANE Select: NM_032040
dbSNP: rs746276818
Type: single nucleotide variant
Location: chr19:46411514 (GRCh38)
Gene constraint: LOEUF 1.796 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 46.83 · 1 PDB
Residue 433: the 'disordered' region

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.Arg433Gln Likely benign 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
CCDC8 p.Arg15Gln Uncertain significance ★★ ⚠ same condition
CCDC8 p.Arg225Gly Uncertain significance ★★ ⚠ same condition
CCDC8 p.Arg277His 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-arg433trp (accessed [today's date]).

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