Is CCDC22 p.Arg135Gln (c.404G>A) pathogenic?

CCDC22 p.Arg135Gln (c.404G>A) is classified Uncertain significance in CCDC22 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-01-26). AlphaMissense: likely benign (0.0727); Very rare (popmax 0.00897%, afr).

How common is CCDC22 p.Arg135Gln (c.404G>A) in the general population?

CCDC22 p.Arg135Gln (c.404G>A) is very rare (popmax 0.00897%, afr) (gnomAD).

What do computational predictors say about CCDC22 p.Arg135Gln (c.404G>A)?

AlphaMissense predicts likely benign (score 0.0727) — an in-silico prediction, not a clinical call.

CCDC22 p.Arg135Gln

c.404G>A · rs782631672 · VCV426293

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0727 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00897%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0727	likely benign
REVEL	0.155	moderately benign-leaning
SaProt	LLR -2.37	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 3.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 5,832 bp · p 0.85 · regional, not allelic
Overall
CADD	20.5	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 0.00897% African / African-American · 5/55,721 alleles

Filtering AF 0.00346% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0022%

Overall 0.00103% 12/1,166,771 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00897%	11,144
European (non-Finnish)	0.000802%	124,625

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.Arg135Gln
Coding: c.404G>A
MANE Select: NM_014008
dbSNP: rs782631672
Type: single nucleotide variant
Location: chrX:49242928 (GRCh38)
Structure: AlphaFold pLDDT 78.95 · 4 PDB
Residue 135: 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

Similar variants

CCDC22 p.Arg135Trp Uncertain significance ★ ⚠ 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.Arg148Cys Uncertain significance ★★ ⚠ same type
CCDC22 p.Arg245Gln Uncertain significance ★★ ⚠ same type
CCDC22 p.Arg257His Uncertain significance ★★ ⚠ same type
CCDC22 p.Arg379Cys 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-arg135gln (accessed [today's date]).

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