Is CCDC166 p.Arg99Pro (c.296G>C) pathogenic?

CCDC166 p.Arg99Pro (c.296G>C) is classified Uncertain significance in CCDC166 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-27). AlphaMissense: likely pathogenic (0.8273); Very rare (popmax 0.00236%, nfe).

How common is CCDC166 p.Arg99Pro (c.296G>C) in the general population?

CCDC166 p.Arg99Pro (c.296G>C) is very rare (popmax 0.00236%, nfe) (gnomAD).

What do computational predictors say about CCDC166 p.Arg99Pro (c.296G>C)?

AlphaMissense predicts likely pathogenic (score 0.8273) — an in-silico prediction, not a clinical call.

CCDC166 p.Arg99Pro

c.296G>C · rs1338759824 · VCV2489423

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8273 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00236%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8273	likely pathogenic · top 4% in CCDC166
REVEL	0.241	benign-leaning
SaProt	LLR -12.99	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 4.3	GERP 1.2, phastCons 1
Overall
CADD	26.9	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 0.00236% European (non-Finnish) · 27/1,146,078 alleles

Filtering AF 0.00161% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00138%

Overall 0.00202% 28/1,387,676 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00236%	42,447
Remaining individualsnot grpmax-eligible	0.00167%	59,950

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.Arg99Pro
Coding: c.296G>C
MANE Select: NM_001162914
dbSNP: rs1338759824
Type: single nucleotide variant
Location: chr8:143707814 (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-arg99pro (accessed [today's date]).

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