Is CCDC22 p.Thr577Ile (c.1730C>T) pathogenic?

CCDC22 p.Thr577Ile (c.1730C>T) is classified Uncertain significance in CCDC22 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-07). AlphaMissense: likely pathogenic (0.7277); Ultra-rare (popmax 0.0299%, mid); Associated with Ritscher-Schinzel syndrome 2.

What condition is associated with CCDC22 p.Thr577Ile (c.1730C>T)?

CCDC22 p.Thr577Ile (c.1730C>T) is associated with Ritscher-Schinzel syndrome 2 (ClinVar).

How common is CCDC22 p.Thr577Ile (c.1730C>T) in the general population?

CCDC22 p.Thr577Ile (c.1730C>T) is ultra-rare (popmax 0.0299%, mid) (gnomAD).

What do computational predictors say about CCDC22 p.Thr577Ile (c.1730C>T)?

AlphaMissense predicts likely pathogenic (score 0.7277) — an in-silico prediction, not a clinical call.

CCDC22 p.Thr577Ile

c.1730C>T · rs1557115091 · VCV1193798

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7277 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0299%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Ritscher-Schinzel syndrome 2

Computational evidence

Protein change
AlphaMissense	0.7277	likely pathogenic
REVEL	0.562	indeterminate
SaProt	LLR -12.22	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.6, 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

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0299% Middle Eastern · 1/3,342 alleles

Filtering AF 0.000105% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.1e-05%

Overall 0.000547% 6/1,096,484 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0299%	3,342
Remaining individualsnot grpmax-eligible	0.0021%	47,518
European (non-Finnish)	0.000447%	223,794

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.Thr577Ile
Coding: c.1730C>T
MANE Select: NM_014008
dbSNP: rs1557115091
Type: single nucleotide variant
Location: chrX:49249685 (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.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
CCDC22 p.Pro187Ser 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-thr577ile (accessed [today's date]).

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