Is ODAD2 p.Arg666Pro (c.1997G>C) pathogenic?

ODAD2 p.Arg666Pro (c.1997G>C) is classified Benign/Likely benign in ODAD2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-15). AlphaMissense: likely pathogenic (0.9851); Rare (popmax 0.458%, afr); Associated with primary ciliary dyskinesia.

What condition is associated with ODAD2 p.Arg666Pro (c.1997G>C)?

ODAD2 p.Arg666Pro (c.1997G>C) is associated with primary ciliary dyskinesia, primary ciliary dyskinesia 23 (ClinVar).

How common is ODAD2 p.Arg666Pro (c.1997G>C) in the general population?

ODAD2 p.Arg666Pro (c.1997G>C) is rare (popmax 0.458%, afr) (gnomAD).

How is Primary ciliary dyskinesia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ODAD2 p.Arg666Pro (c.1997G>C)?

AlphaMissense predicts likely pathogenic (score 0.9851) — an in-silico prediction, not a clinical call.

ODAD2 p.Arg666Pro

c.1997G>C · rs35472668 · VCV698302

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9851 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.458%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.9851	likely pathogenic · top 2% in ODAD2
REVEL	0.831	moderately pathogenic-leaning
SaProt	LLR -17.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 132 kb · p 0.67 · regional, not allelic
Overall
CADD	27.2	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 0.458% African / African-American · 340/74,252 alleles

Filtering AF 0.418% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.402%

Overall 0.0234% 375/1,602,990 alleles · rare exomes 188/1,450,914 · genomes 187/152,076 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.458%	218
Remaining individualsnot grpmax-eligible	0.0242%	4,132
Admixed American	0.0241%	4,152
Middle Eastern	0.0166%	6,026
European (non-Finnish)	0.000425%	235,018

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: ODAD2
Protein: p.Arg666Pro
Coding: c.1997G>C
MANE Select: NM_018076
dbSNP: rs35472668
Type: single nucleotide variant
Location: chr10:27939997 (GRCh38)
Gene constraint: LOEUF 0.977 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.63 · 1 PDB

Full ODAD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

primary ciliary dyskinesia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: primary ciliary dyskinesia 23

For Primary ciliary dyskinesia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Neonatal
Prevalence: 1-5 / 10 000 (Pakistan)

Similar variants

ODAD2 p.Arg666Gln Benign/Likely benign ★★ ⚠ same residue
ODAD2 p.Arg666Trp Uncertain significance ★ ⚠ same residue
ODAD2 c.2097+1G>A Pathogenic/Likely pathogenic ★★ same condition
ODAD2 c.2097+1G>T Pathogenic/Likely pathogenic ★★ same condition
ODAD2 c.2495+1G>A Pathogenic ★★ same condition
ODAD2 c.2800-2A>G Pathogenic/Likely pathogenic ★★ same condition
ODAD2 c.383-1G>T Likely pathogenic ★★ same condition
ODAD2 c.576-2A>T Likely pathogenic ★★ same condition

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/odad2-p-arg666pro (accessed [today's date]).

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