Is CCDC8 p.Ala446Ser (c.1336G>T) pathogenic?

CCDC8 p.Ala446Ser (c.1336G>T) is classified Uncertain significance in CCDC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-30). AlphaMissense: likely benign (0.0823); Very rare (popmax 0.00178%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CCDC8 p.Ala446Ser (c.1336G>T)?

CCDC8 p.Ala446Ser (c.1336G>T) is associated with Inborn genetic diseases (ClinVar).

How common is CCDC8 p.Ala446Ser (c.1336G>T) in the general population?

CCDC8 p.Ala446Ser (c.1336G>T) is very rare (popmax 0.00178%, nfe) (gnomAD).

What do computational predictors say about CCDC8 p.Ala446Ser (c.1336G>T)?

AlphaMissense predicts likely benign (score 0.0823) — an in-silico prediction, not a clinical call.

CCDC8 p.Ala446Ser

c.1336G>T · rs539275231 · VCV3139409

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0823 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0823	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -9.63	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 0.63	GERP -0.011, phastCons 0.004
Regional constraint	o/e 1.02	unconstrained · MANE · 1,613 bp · p 0.66 · regional, not allelic
Overall
CADD	17.06	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 0.00178% European (non-Finnish) · 21/1,180,034 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.0013% 21/1,614,118 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.Ala446Ser
Coding: c.1336G>T
MANE Select: NM_032040
dbSNP: rs539275231
Type: single nucleotide variant
Location: chr19:46411475 (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 446: 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.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-ala446ser (accessed [today's date]).

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