Is CWC22 p.Pro40Arg (c.119C>G) pathogenic?

CWC22 p.Pro40Arg (c.119C>G) is classified Uncertain significance in CWC22 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-23). AlphaMissense: likely benign (0.0768); Ultra-rare (popmax 0.0282%, amr).

How common is CWC22 p.Pro40Arg (c.119C>G) in the general population?

CWC22 p.Pro40Arg (c.119C>G) is ultra-rare (popmax 0.0282%, amr) (gnomAD).

What do computational predictors say about CWC22 p.Pro40Arg (c.119C>G)?

AlphaMissense predicts likely benign (score 0.0768) — an in-silico prediction, not a clinical call.

CWC22 p.Pro40Arg

c.119C>G · rs761538099 · VCV3079078

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0768 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0282%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0768	likely benign
REVEL	0.198	benign-leaning
SaProt	LLR -4.24	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 11	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 38 kb · p 0.078 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0282% Admixed American · 16/56,766 alleles

Filtering AF 0.0176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0143%

Overall 0.00113% 18/1,594,050 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0282%	3,548
Remaining individualsnot grpmax-eligible	0.00162%	61,716
African / African-American	0.00135%	73,990

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: CWC22
Protein: p.Pro40Arg
Coding: c.119C>G
MANE Select: NM_020943
dbSNP: rs761538099
Type: single nucleotide variant
Location: chr2:179986782 (GRCh38)
Gene constraint: LOEUF 0.875 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.00 · 29 PDB
Residue 40: the 'disordered' region

Full CWC22 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CWC22 p.Pro40Leu Uncertain significance ★ ⚠ same residue
CWC22 p.Asp741Val Benign ★★ same type
CWC22 p.Gln365= Benign ★★ same type
CWC22 p.Ala419Thr Uncertain significance ★ ⚠ same type
CWC22 p.Ala674Ser Uncertain significance ★ ⚠ same type
CWC22 p.Arg128Pro Uncertain significance ★ ⚠ same type
CWC22 p.Arg156Lys Uncertain significance ★ ⚠ same type
CWC22 p.Arg17Thr 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/cwc22-p-pro40arg (accessed [today's date]).

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