Is CCDC22 p.Arg66His (c.197G>A) pathogenic?

CCDC22 p.Arg66His (c.197G>A) is classified Uncertain significance in CCDC22 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-01). AlphaMissense: ambiguous (0.4); Very rare (popmax 0.00435%, amr); Associated with Ritscher-Schinzel syndrome 2.

What condition is associated with CCDC22 p.Arg66His (c.197G>A)?

CCDC22 p.Arg66His (c.197G>A) is associated with Ritscher-Schinzel syndrome 2 (ClinVar).

How common is CCDC22 p.Arg66His (c.197G>A) in the general population?

CCDC22 p.Arg66His (c.197G>A) is very rare (popmax 0.00435%, amr) (gnomAD).

What do computational predictors say about CCDC22 p.Arg66His (c.197G>A)?

AlphaMissense predicts ambiguous (score 0.4) — an in-silico prediction, not a clinical call.

CCDC22 p.Arg66His

c.197G>A · rs199545573 · VCV638386

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00435%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Ritscher-Schinzel syndrome 2

Computational evidence

Protein change
AlphaMissense	0.4	ambiguous
REVEL	0.71	pathogenic-leaning
SaProt	LLR -9.42	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.52	unconstrained · MANE · 7,249 bp · p 7.2e-07 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00435% Admixed American · 2/45,937 alleles

Filtering AF 0.000722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00027%

Overall 0.000744% 9/1,209,176 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00435%	22,968
Remaining individualsnot grpmax-eligible	0.0021%	47,579
African / African-American	0.00173%	57,670
European (non-Finnish)	0.000559%	178,899

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.Arg66His
Coding: c.197G>A
MANE Select: NM_014008
dbSNP: rs199545573
Type: single nucleotide variant
Location: chrX:49237232 (GRCh38)
Structure: AlphaFold pLDDT 78.95 · 4 PDB
Residue 66: the 'sufficicient and required for interaction with ccdc93' region; 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.Arg245Gln Uncertain significance ★★ ⚠ same condition
CCDC22 p.Arg623Trp Uncertain significance ★★ ⚠ same condition
CCDC22 p.Arg625Trp 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-arg66his (accessed [today's date]).

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