Is CCDC66 p.Pro643Ser (c.1927C>T) pathogenic?

CCDC66 p.Pro643Ser (c.1927C>T) is classified Uncertain significance in CCDC66 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-12). AlphaMissense: likely benign (0.1555); Very rare (popmax 0.00339%, nfe).

How common is CCDC66 p.Pro643Ser (c.1927C>T) in the general population?

CCDC66 p.Pro643Ser (c.1927C>T) is very rare (popmax 0.00339%, nfe) (gnomAD).

What do computational predictors say about CCDC66 p.Pro643Ser (c.1927C>T)?

AlphaMissense predicts likely benign (score 0.1555) — an in-silico prediction, not a clinical call.

CCDC66 p.Pro643Ser

c.1927C>T · rs764323696 · VCV2218470

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1555 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00339%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1555	likely benign
REVEL	0.188	benign-leaning
SaProt	LLR -5.32	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 3.2	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 64 kb · p 0.12 · regional, not allelic
Overall
CADD	21.0	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 0.00339% European (non-Finnish) · 40/1,179,750 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00248% 40/1,613,170 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: CCDC66
Protein: p.Pro643Ser
Coding: c.1927C>T
MANE Select: NM_001141947
dbSNP: rs764323696
Type: single nucleotide variant
Location: chr3:56617195 (GRCh38)
Gene constraint: LOEUF 1.135 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.56
Residue 643: the 'mediates localization to cilia, centrosomes and spindle microtubules and the interaction with pcm1, cep290, cep104 and cspp1' region

Full CCDC66 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC66 p.Ala114Val Uncertain significance ★ ⚠ same type
CCDC66 p.Ala142Gly Uncertain significance ★ ⚠ same type
CCDC66 p.Ala323Thr Uncertain significance ★ ⚠ same type
CCDC66 p.Ala668Pro Uncertain significance ★ ⚠ same type
CCDC66 p.Ala937Val Uncertain significance ★ ⚠ same type
CCDC66 p.Arg122Ser Uncertain significance ★ ⚠ same type
CCDC66 p.Arg443Cys Uncertain significance ★ ⚠ same type
CCDC66 p.Arg443His 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/ccdc66-p-pro643ser (accessed [today's date]).

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