Is CCDC166 p.Ile220Val (c.658A>G) pathogenic?

CCDC166 p.Ile220Val (c.658A>G) is classified Uncertain significance in CCDC166 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). AlphaMissense: likely benign (0.1266); Ultra-rare (popmax 0.0301%, eas).

How common is CCDC166 p.Ile220Val (c.658A>G) in the general population?

CCDC166 p.Ile220Val (c.658A>G) is ultra-rare (popmax 0.0301%, eas) (gnomAD).

What do computational predictors say about CCDC166 p.Ile220Val (c.658A>G)?

AlphaMissense predicts likely benign (score 0.1266) — an in-silico prediction, not a clinical call.

CCDC166 p.Ile220Val

c.658A>G · rs1217106768 · VCV3138624

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1266 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0301%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1266	likely benign
REVEL	0.009	strongly benign-leaning
SaProt	LLR -4.84	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 -0.49	GERP -1.9, phastCons 0.074
Overall
CADD	11.44	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 0.0301% East Asian · 10/33,196 alleles

Filtering AF 0.0163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.000855% 12/1,403,896 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0301%	3,320
Admixed American	0.00338%	29,628
European (non-Finnish)	9.22e-05%	1,084,412

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.Ile220Val
Coding: c.658A>G
MANE Select: NM_001162914
dbSNP: rs1217106768
Type: single nucleotide variant
Location: chr8:143707356 (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-ile220val (accessed [today's date]).

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