Is CWC22 p.Ala674Ser (c.2020G>T) pathogenic?

CWC22 p.Ala674Ser (c.2020G>T) is classified Uncertain significance in CWC22 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely benign (0.0602); Very rare (popmax 0.00017%, nfe).

How common is CWC22 p.Ala674Ser (c.2020G>T) in the general population?

CWC22 p.Ala674Ser (c.2020G>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about CWC22 p.Ala674Ser (c.2020G>T)?

AlphaMissense predicts likely benign (score 0.0602) — an in-silico prediction, not a clinical call.

CWC22 p.Ala674Ser

c.2020G>T · VCV4236295

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0602 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0602	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -0.88	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.59	acceptor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.88	GERP -0.009
Regional constraint	o/e 1.03	unconstrained · MANE · 5,577 bp · p 0.59 · regional, not allelic
Overall
CADD	12.56	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 0.00017% European (non-Finnish) · 2/1,179,620 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,368 alleles · very rare

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.Ala674Ser
Coding: c.2020G>T
MANE Select: NM_020943
Type: single nucleotide variant
Location: chr2:179950632 (GRCh38)
Gene constraint: LOEUF 0.875 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.00 · 29 PDB
Residue 674: the 'disordered' region

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

Similar variants

CWC22 p.Asp741Val Benign ★★ same type
CWC22 p.Gln365= Benign ★★ same type
CWC22 p.Ala419Thr 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
CWC22 p.Arg236Thr Uncertain significance ★ ⚠ same type
CWC22 p.Arg246Gln 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-ala674ser (accessed [today's date]).

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