Is CCDC22 p.Arg135Trp (c.403C>T) pathogenic?

CCDC22 p.Arg135Trp (c.403C>T) is classified Uncertain significance in CCDC22 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-01-23). AlphaMissense: likely benign (0.1165); Very rare (popmax 0.0099%, sas); Associated with intellectual disability.

What condition is associated with CCDC22 p.Arg135Trp (c.403C>T)?

CCDC22 p.Arg135Trp (c.403C>T) is associated with intellectual disability (ClinVar).

How common is CCDC22 p.Arg135Trp (c.403C>T) in the general population?

CCDC22 p.Arg135Trp (c.403C>T) is very rare (popmax 0.0099%, sas) (gnomAD).

What do computational predictors say about CCDC22 p.Arg135Trp (c.403C>T)?

AlphaMissense predicts likely benign (score 0.1165) — an in-silico prediction, not a clinical call.

CCDC22 p.Arg135Trp

c.403C>T · rs1557113578 · VCV975509

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1165 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0099%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability

Computational evidence

Protein change
AlphaMissense	0.1165	likely benign
REVEL	0.216	benign-leaning
SaProt	LLR -5.82	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 0.6	GERP -0.81, phastCons 0.81
Regional constraint	o/e 0.99	unconstrained · MANE · 5,832 bp · p 0.85 · regional, not allelic
Overall
CADD	21.6	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 0.0099% South Asian · 5/50,496 alleles

Filtering AF 0.00385% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0025%

Overall 0.000757% 8/1,056,530 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0099%	10,099
East Asian	0.00612%	16,352
European (non-Finnish)	0.000115%	873,347

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.Arg135Trp
Coding: c.403C>T
MANE Select: NM_014008
dbSNP: rs1557113578
Type: single nucleotide variant
Location: chrX:49242927 (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

Disease context

intellectual disability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CCDC22 p.Arg135Gln Uncertain significance ★★ ⚠ same residue
CCDC22 p.Arg496Cys Uncertain significance ★★ ⚠ same condition
CCDC22 c.536-7C>T Benign/Likely benign ★★ same condition
CCDC22 p.Asp546Asn Benign/Likely benign ★★ same condition
CCDC22 p.Arg384Cys Conflicting classifications of pathogenicity ★ ⚠ same condition
CCDC22 p.Thr232Pro Conflicting classifications of pathogenicity ★ ⚠ same condition
CCDC22 c.909+8C>T Likely benign same condition
CCDC22 p.Ala463Gly 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-arg135trp (accessed [today's date]).

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