Is CCDC8 p.Ala293Val (c.878C>T) pathogenic?

CCDC8 p.Ala293Val (c.878C>T) is classified Uncertain significance in CCDC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: likely benign (0.1219); Very rare (popmax 0.00102%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CCDC8 p.Ala293Val (c.878C>T)?

CCDC8 p.Ala293Val (c.878C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CCDC8 p.Ala293Val (c.878C>T) in the general population?

CCDC8 p.Ala293Val (c.878C>T) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about CCDC8 p.Ala293Val (c.878C>T)?

AlphaMissense predicts likely benign (score 0.1219) — an in-silico prediction, not a clinical call.

CCDC8 p.Ala293Val

c.878C>T · VCV4606984

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1219 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1219	likely benign
REVEL	0.013	strongly benign-leaning
SaProt	LLR -8.17	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 -3.5	GERP -2.3
Regional constraint	o/e 1.02	unconstrained · MANE · 1,613 bp · p 0.66 · regional, not allelic
Overall
CADD	5.748	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 0.00102% European (non-Finnish) · 12/1,179,080 alleles

Filtering AF 0.000543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000429%

Overall 0.000891% 13/1,459,102 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,406
European (non-Finnish)grpmax	0.00102%	98,257

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala293Val
Coding: c.878C>T
MANE Select: NM_032040
Type: single nucleotide variant
Location: chr19:46411933 (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 293: 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.Ala293Thr Uncertain significance ★★ ⚠ same residue
CCDC8 p.Ala217Thr 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-ala293val (accessed [today's date]).

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