Is CCDC22 p.Ala618Pro (c.1852G>C) pathogenic?

CCDC22 p.Ala618Pro (c.1852G>C) is classified Uncertain significance in CCDC22 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-16). AlphaMissense: likely pathogenic (0.9255); Absent from gnomAD v4.1; Associated with Ritscher-Schinzel syndrome 2.

What condition is associated with CCDC22 p.Ala618Pro (c.1852G>C)?

CCDC22 p.Ala618Pro (c.1852G>C) is associated with Ritscher-Schinzel syndrome 2 (ClinVar).

How common is CCDC22 p.Ala618Pro (c.1852G>C) in the general population?

CCDC22 p.Ala618Pro (c.1852G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CCDC22 p.Ala618Pro (c.1852G>C)?

AlphaMissense predicts likely pathogenic (score 0.9255) — an in-silico prediction, not a clinical call.

CCDC22 p.Ala618Pro

c.1852G>C · rs2519183077 · VCV2431770

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9255 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ritscher-Schinzel syndrome 2

Computational evidence

Protein change
AlphaMissense	0.9255	likely pathogenic · top 8% in CCDC22
REVEL	0.168	moderately benign-leaning
SaProt	LLR -13.05	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 0.39, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 582 bp · p 0.38 · regional, not allelic
Overall
CADD	25.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CCDC22
Protein: p.Ala618Pro
Coding: c.1852G>C
MANE Select: NM_014008
dbSNP: rs2519183077
Type: single nucleotide variant
Location: chrX:49250229 (GRCh38)
Structure: AlphaFold pLDDT 78.95 · 4 PDB

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.Ala618Thr Uncertain significance ★ ⚠ same residue
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.Arg66His 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-ala618pro (accessed [today's date]).

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