Is CWC22 p.Ser176Pro (c.526T>C) pathogenic?

CWC22 p.Ser176Pro (c.526T>C) is classified Uncertain significance in CWC22 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-23). AlphaMissense: likely pathogenic (0.6046); Ultra-rare (popmax 0.0345%, mid).

How common is CWC22 p.Ser176Pro (c.526T>C) in the general population?

CWC22 p.Ser176Pro (c.526T>C) is ultra-rare (popmax 0.0345%, mid) (gnomAD).

What do computational predictors say about CWC22 p.Ser176Pro (c.526T>C)?

AlphaMissense predicts likely pathogenic (score 0.6046) — an in-silico prediction, not a clinical call.

CWC22 p.Ser176Pro

c.526T>C · VCV4236286

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6046 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0345%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6046	likely pathogenic
REVEL	0.331	indeterminate
SaProt	LLR -13.37	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 9.4	GERP 0.72, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 38 kb · p 0.078 · regional, not allelic
Overall
CADD	28.0	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 0.0345% Middle Eastern · 2/5,802 alleles

Filtering AF 0.00606% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00251%

Overall 0.000572% 9/1,574,382 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0345%	2,901
Admixed American	0.00184%	54,254
Remaining individualsnot grpmax-eligible	0.00165%	60,610
European (non-Finnish)	0.00043%	232,395

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.Ser176Pro
Coding: c.526T>C
MANE Select: NM_020943
Type: single nucleotide variant
Location: chr2:179978245 (GRCh38)
Gene constraint: LOEUF 0.875 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.00 · 29 PDB
Residue 176: the mif4g domain; a turn

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.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
CWC22 p.Arg236Thr 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-ser176pro (accessed [today's date]).

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