Is CCDC22 p.Arg181Gln (c.542G>A) pathogenic?

CCDC22 p.Arg181Gln (c.542G>A) is classified Uncertain significance in CCDC22 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-22). AlphaMissense: likely benign (0.0745); Very rare (popmax 0.0035%, afr); Associated with Ritscher-Schinzel syndrome 2.

What condition is associated with CCDC22 p.Arg181Gln (c.542G>A)?

CCDC22 p.Arg181Gln (c.542G>A) is associated with Ritscher-Schinzel syndrome 2 (ClinVar).

How common is CCDC22 p.Arg181Gln (c.542G>A) in the general population?

CCDC22 p.Arg181Gln (c.542G>A) is very rare (popmax 0.0035%, afr) (gnomAD).

What do computational predictors say about CCDC22 p.Arg181Gln (c.542G>A)?

AlphaMissense predicts likely benign (score 0.0745) — an in-silico prediction, not a clinical call.

CCDC22 p.Arg181Gln

c.542G>A · rs782815473 · VCV2439795

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0745 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0035%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ritscher-Schinzel syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0745	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -5.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.34	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 2.1	GERP -2.1, phastCons 0.88
Regional constraint	o/e 0.99	unconstrained · MANE · 5,832 bp · p 0.85 · regional, not allelic
Overall
CADD	20.4	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 0.0035% African / African-American · 2/57,186 alleles

Filtering AF 0.00058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000217%

Overall 0.000501% 6/1,198,477 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0035%	28,593
East Asian	0.00299%	33,469
European (non-Finnish)	0.000338%	296,193

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: CCDC22
Protein: p.Arg181Gln
Coding: c.542G>A
MANE Select: NM_014008
dbSNP: rs782815473
Type: single nucleotide variant
Location: chrX:49243290 (GRCh38)
Structure: AlphaFold pLDDT 78.95 · 4 PDB
Residue 181: the 'sufficicient and required for interaction with ccdc93' region; an α-helix; the 'sufficient for interaction with commd1' region

Full CCDC22 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Ritscher-Schinzel syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CCDC22 p.Arg181Trp Uncertain significance ★ ⚠ same residue
CCDC22 p.Ala463Gly Uncertain significance ★★ ⚠ same condition
CCDC22 p.Arg107Cys Uncertain significance ★★ ⚠ same condition
CCDC22 p.Arg128Gln Uncertain significance ★★ ⚠ same condition
CCDC22 p.Arg245Gln Uncertain significance ★★ ⚠ same condition
CCDC22 p.Arg623Trp Uncertain significance ★★ ⚠ same condition
CCDC22 p.Arg625Trp Uncertain significance ★★ ⚠ same condition
CCDC22 p.Arg66His Uncertain significance ★★ ⚠ 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/ccdc22-p-arg181gln (accessed [today's date]).

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