Is CWC22 p.Pro617Ser (c.1849C>T) pathogenic?

CWC22 p.Pro617Ser (c.1849C>T) is classified Uncertain significance in CWC22 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-16). AlphaMissense: likely pathogenic (0.9977); Very rare (popmax 0.00463%, eas).

How common is CWC22 p.Pro617Ser (c.1849C>T) in the general population?

CWC22 p.Pro617Ser (c.1849C>T) is very rare (popmax 0.00463%, eas) (gnomAD).

What do computational predictors say about CWC22 p.Pro617Ser (c.1849C>T)?

AlphaMissense predicts likely pathogenic (score 0.9977) — an in-silico prediction, not a clinical call.

CWC22 p.Pro617Ser

c.1849C>T · VCV3270366

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00463%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9977	likely pathogenic · top 9% in CWC22
REVEL	0.587	indeterminate
SaProt	LLR -13.20	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 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 4,266 bp · p 2.6e-05 · regional, not allelic
Overall
CADD	28.1	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 0.00463% East Asian · 2/43,238 alleles

Filtering AF 0.000767% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000287%

Overall 0.00014% 2/1,428,708 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.Pro617Ser
Coding: c.1849C>T
MANE Select: NM_020943
Type: single nucleotide variant
Location: chr2:179950895 (GRCh38)
Gene constraint: LOEUF 0.875 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.00 · 29 PDB

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-pro617ser (accessed [today's date]).

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