Is CCDC22 p.Glu378Asp (c.1134G>C) pathogenic?

CCDC22 p.Glu378Asp (c.1134G>C) is classified Conflicting classifications of pathogenicity in CCDC22 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-11-01). AlphaMissense: likely benign (0.1768); Ultra-rare (popmax 0.0486%, nfe).

How common is CCDC22 p.Glu378Asp (c.1134G>C) in the general population?

CCDC22 p.Glu378Asp (c.1134G>C) is ultra-rare (popmax 0.0486%, nfe) (gnomAD).

What do computational predictors say about CCDC22 p.Glu378Asp (c.1134G>C)?

AlphaMissense predicts likely benign (score 0.1768) — an in-silico prediction, not a clinical call.

CCDC22 p.Glu378Asp

c.1134G>C · rs199995957 · VCV2338674

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1768 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0486%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1768	likely benign
REVEL	0.227	benign-leaning
SaProt	LLR -7.58	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 3.3	GERP 1.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 5,832 bp · p 0.85 · regional, not allelic
Overall
CADD	16.46	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 0.0486% European (non-Finnish) · 435/894,762 alleles

Filtering AF 0.0448% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0433%

Overall 0.0395% 476/1,203,646 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0486%	2,057
Remaining individualsnot grpmax-eligible	0.0442%	2,260
Finnishnot grpmax-eligible	0.0384%	2,604
African / African-American	0.00528%	18,939
Admixed American	0.00219%	45,753

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.Glu378Asp
Coding: c.1134G>C
MANE Select: NM_014008
dbSNP: rs199995957
Type: single nucleotide variant
Location: chrX:49248232 (GRCh38)
Structure: AlphaFold pLDDT 78.95 · 4 PDB
Residue 378: the 'sufficicient and required for interaction with ccdc93' region

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

Similar variants

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
CCDC22 p.Arg379Cys 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-glu378asp (accessed [today's date]).

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