Is CCDC166 p.Leu69Pro (c.206T>C) pathogenic?

CCDC166 p.Leu69Pro (c.206T>C) is classified Uncertain significance in CCDC166 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-16). AlphaMissense: likely pathogenic (0.9558); Rare (popmax 0.118%, eas).

How common is CCDC166 p.Leu69Pro (c.206T>C) in the general population?

CCDC166 p.Leu69Pro (c.206T>C) is rare (popmax 0.118%, eas) (gnomAD).

What do computational predictors say about CCDC166 p.Leu69Pro (c.206T>C)?

AlphaMissense predicts likely pathogenic (score 0.9558) — an in-silico prediction, not a clinical call.

CCDC166 p.Leu69Pro

c.206T>C · rs782492779 · VCV2392053

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9558 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.118%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9558	likely pathogenic · top 1% in CCDC166
REVEL	0.154	moderately benign-leaning
SaProt	LLR -14.91	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.8, phastCons 1
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.118% East Asian · 48/40,830 alleles

Filtering AF 0.091% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0817%

Overall 0.00982% 151/1,537,586 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.118%	851
South Asian	0.0535%	1,868
Ashkenazi Jewishnot grpmax-eligible	0.0384%	2,602
Remaining individualsnot grpmax-eligible	0.0217%	4,614
Middle Eastern	0.0168%	5,966
European (non-Finnish)	0.00288%	34,743

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: CCDC166
Protein: p.Leu69Pro
Coding: c.206T>C
MANE Select: NM_001162914
dbSNP: rs782492779
Type: single nucleotide variant
Location: chr8:143707904 (GRCh38)
Gene constraint: LOEUF 1.939 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.10

Full CCDC166 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC166 p.Ala113Asp Uncertain significance ★ ⚠ same type
CCDC166 p.Ala219Val Uncertain significance ★ ⚠ same type
CCDC166 p.Ala222Ser Uncertain significance ★ ⚠ same type
CCDC166 p.Ala31Thr Uncertain significance ★ ⚠ same type
CCDC166 p.Ala39Ser Uncertain significance ★ ⚠ same type
CCDC166 p.Ala430Asp Uncertain significance ★ ⚠ same type
CCDC166 p.Ala434Val Uncertain significance ★ ⚠ same type
CCDC166 p.Arg119Gly 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/ccdc166-p-leu69pro (accessed [today's date]).

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