Is CCDC66 p.Ile687Arg (c.2060T>G) pathogenic?

CCDC66 p.Ile687Arg (c.2060T>G) is classified Uncertain significance in CCDC66 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-20). AlphaMissense: likely benign (0.0766); Very rare (popmax 0.00924%, nfe).

How common is CCDC66 p.Ile687Arg (c.2060T>G) in the general population?

CCDC66 p.Ile687Arg (c.2060T>G) is very rare (popmax 0.00924%, nfe) (gnomAD).

What do computational predictors say about CCDC66 p.Ile687Arg (c.2060T>G)?

AlphaMissense predicts likely benign (score 0.0766) — an in-silico prediction, not a clinical call.

CCDC66 p.Ile687Arg

c.2060T>G · rs200755390 · VCV2375089

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0766 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00924%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0766	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -6.23	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 0.016	GERP 0.054, phastCons 0.058
Regional constraint	o/e 1.05	unconstrained · MANE · 64 kb · p 0.12 · regional, not allelic
Overall
CADD	15.65	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 0.00924% European (non-Finnish) · 109/1,179,640 alleles

Filtering AF 0.00783% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00728%

Overall 0.00719% 116/1,612,274 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00924%	10,822
Remaining individualsnot grpmax-eligible	0.00641%	15,605
Finnishnot grpmax-eligible	0.00469%	21,316

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.Ile687Arg
Coding: c.2060T>G
MANE Select: NM_001141947
dbSNP: rs200755390
Type: single nucleotide variant
Location: chr3:56617328 (GRCh38)
Gene constraint: LOEUF 1.135 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.56
Residue 687: 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-ile687arg (accessed [today's date]).

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