Is CWC27 p.Thr19Ser (c.56C>G) pathogenic?

CWC27 p.Thr19Ser (c.56C>G) is classified Uncertain significance in CWC27 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-05). AlphaMissense: likely pathogenic (0.907); Very rare (popmax 8.61e-05%, nfe).

How common is CWC27 p.Thr19Ser (c.56C>G) in the general population?

CWC27 p.Thr19Ser (c.56C>G) is very rare (popmax 8.61e-05%, nfe) (gnomAD).

What do computational predictors say about CWC27 p.Thr19Ser (c.56C>G)?

AlphaMissense predicts likely pathogenic (score 0.907) — an in-silico prediction, not a clinical call.

CWC27 p.Thr19Ser

c.56C>G · rs1743379463 · VCV2150347

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.907 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.61e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.907	likely pathogenic
REVEL	0.514	indeterminate
SaProt	LLR -10.61	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 7.6	GERP 5.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 249 kb · p 0.12 · regional, not allelic
Overall
CADD	27.5	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 8.61e-05% European (non-Finnish) · 1/1,161,320 alleles

Overall 7.05e-05% 1/1,419,044 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: CWC27
Protein: p.Thr19Ser
Coding: c.56C>G
MANE Select: NM_005869
dbSNP: rs1743379463
Type: single nucleotide variant
Location: chr5:64774704 (GRCh38)
Gene constraint: LOEUF 1.181 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.93 · 9 PDB
Residue 19: the ppiase cyclophilin-type domain; a UniProt-annotated variant site (in rpska); a β-strand

Full CWC27 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CWC27 c.1152+2T>A Likely pathogenic ★★ same type
CWC27 c.397-1G>A Likely pathogenic ★★ same type
CWC27 c.938+2T>C Likely pathogenic ★★ same type
CWC27 p.Arg143Ter Pathogenic/Likely pathogenic ★★ same type
CWC27 p.Gln374Ter Pathogenic/Likely pathogenic ★★ same type
CWC27 p.Glu165= Pathogenic ★★ same type
CWC27 p.Tyr367Ter Pathogenic/Likely pathogenic ★★ same type
CWC27 c.1042+5G>A 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/cwc27-p-thr19ser (accessed [today's date]).

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