Is CCDC22 p.Arg220Trp (c.658C>T) pathogenic?

CCDC22 p.Arg220Trp (c.658C>T) is classified Uncertain significance in CCDC22 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-24). AlphaMissense: likely benign (0.0701); Ultra-rare (popmax 0.0231%, mid).

How common is CCDC22 p.Arg220Trp (c.658C>T) in the general population?

CCDC22 p.Arg220Trp (c.658C>T) is ultra-rare (popmax 0.0231%, mid) (gnomAD).

What do computational predictors say about CCDC22 p.Arg220Trp (c.658C>T)?

AlphaMissense predicts likely benign (score 0.0701) — an in-silico prediction, not a clinical call.

CCDC22 p.Arg220Trp

c.658C>T · VCV3996894

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0701 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0231%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0701	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -8.53	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 0.18	GERP 1.4
Regional constraint	o/e 0.99	unconstrained · MANE · 5,832 bp · p 0.85 · regional, not allelic
Overall
CADD	10.69	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 0.0231% Middle Eastern · 1/4,323 alleles

Filtering AF 0.00238% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00126%

Overall 0.0025% 30/1,201,964 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0231%	4,323
East Asian	0.00898%	11,139
South Asian	0.00542%	18,451
Admixed American	0.00444%	22,526
European (non-Finnish)	0.00213%	46,898
Remaining individualsnot grpmax-eligible	0.00212%	47,248
African / African-American	0.00175%	57,208

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.Arg220Trp
Coding: c.658C>T
MANE Select: NM_014008
Type: single nucleotide variant
Location: chrX:49243406 (GRCh38)
Structure: AlphaFold pLDDT 78.95 · 4 PDB
Residue 220: the 'sufficicient and required for interaction with ccdc93' region; the 'sufficient for interaction with commd1' region; the 'disordered' region

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

Similar variants

CCDC22 p.Arg220Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CCDC22 p.Ala463Gly Uncertain significance ★★ ⚠ same type
CCDC22 p.Arg107Cys Uncertain significance ★★ ⚠ same type
CCDC22 p.Arg128Gln Uncertain significance ★★ ⚠ same type
CCDC22 p.Arg135Gln Uncertain significance ★★ ⚠ same type
CCDC22 p.Arg148Cys Uncertain significance ★★ ⚠ same type
CCDC22 p.Arg245Gln Uncertain significance ★★ ⚠ same type
CCDC22 p.Arg257His 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/ccdc22-p-arg220trp (accessed [today's date]).

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