Is CCDC22 p.Arg245Gln (c.734G>A) pathogenic?

CCDC22 p.Arg245Gln (c.734G>A) is classified Uncertain significance in CCDC22 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-02). AlphaMissense: likely benign (0.0704); Very rare (popmax 0.00391%, nfe); Associated with Ritscher-Schinzel syndrome 2.

What condition is associated with CCDC22 p.Arg245Gln (c.734G>A)?

CCDC22 p.Arg245Gln (c.734G>A) is associated with Ritscher-Schinzel syndrome 2 (ClinVar).

How common is CCDC22 p.Arg245Gln (c.734G>A) in the general population?

CCDC22 p.Arg245Gln (c.734G>A) is very rare (popmax 0.00391%, nfe) (gnomAD).

What do computational predictors say about CCDC22 p.Arg245Gln (c.734G>A)?

AlphaMissense predicts likely benign (score 0.0704) — an in-silico prediction, not a clinical call.

CCDC22 p.Arg245Gln

c.734G>A · VCV3486585

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0704 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00391%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ritscher-Schinzel syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0704	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -5.76	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 2	GERP -0.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 5,832 bp · p 0.85 · regional, not allelic
Overall
CADD	11.61	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 0.00391% European (non-Finnish) · 34/870,163 alleles

Filtering AF 0.00281% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00248%

Overall 0.00353% 37/1,049,047 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00441%	22,674
European (non-Finnish)grpmax	0.00391%	25,593
Admixed American	0.00244%	41,019

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg245Gln
Coding: c.734G>A
MANE Select: NM_014008
Type: single nucleotide variant
Location: chrX:49246750 (GRCh38)
Structure: AlphaFold pLDDT 78.95 · 4 PDB
Residue 245: 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.Ala463Gly Uncertain significance ★★ ⚠ same condition
CCDC22 p.Arg107Cys Uncertain significance ★★ ⚠ same condition
CCDC22 p.Arg128Gln 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
CCDC22 p.Pro187Ser Uncertain significance ★★ ⚠ same condition
CCDC22 p.Thr577Ile 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-arg245gln (accessed [today's date]).

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