Is CCDC22 p.Ser529Pro (c.1585T>C) pathogenic?

CCDC22 p.Ser529Pro (c.1585T>C) is classified Uncertain significance in CCDC22 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-11). AlphaMissense: likely pathogenic (0.9334); Very rare (popmax 0.00101%, nfe).

How common is CCDC22 p.Ser529Pro (c.1585T>C) in the general population?

CCDC22 p.Ser529Pro (c.1585T>C) is very rare (popmax 0.00101%, nfe) (gnomAD).

What do computational predictors say about CCDC22 p.Ser529Pro (c.1585T>C)?

AlphaMissense predicts likely pathogenic (score 0.9334) — an in-silico prediction, not a clinical call.

CCDC22 p.Ser529Pro

c.1585T>C · rs200528517 · VCV2602979

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9334 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00101%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9334	likely pathogenic · top 8% in CCDC22
REVEL	0.272	benign-leaning
SaProt	LLR -14.32	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 4.2	GERP 1.6, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 955 bp · p 0.00011 · regional, not allelic
Overall
CADD	25.8	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 0.00101% European (non-Finnish) · 9/894,429 alleles

Filtering AF 0.000473% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000343%

Overall 0.00347% 42/1,209,435 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0687%	1,456
Remaining individualsnot grpmax-eligible	0.0021%	47,607
European (non-Finnish)grpmax	0.00101%	99,381

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser529Pro
Coding: c.1585T>C
MANE Select: NM_014008
dbSNP: rs200528517
Type: single nucleotide variant
Location: chrX:49249212 (GRCh38)
Structure: AlphaFold pLDDT 78.95 · 4 PDB

Full CCDC22 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC22 p.Ser529Tyr 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.Arg135Gln 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

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-ser529pro (accessed [today's date]).

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