Is CWC27 p.Ser89Pro (c.265T>C) pathogenic?

CWC27 p.Ser89Pro (c.265T>C) is classified Uncertain significance in CWC27 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-12-02). AlphaMissense: likely pathogenic (0.8105); Very rare (popmax 0.00551%, afr); Associated with Inborn genetic diseases.

What condition is associated with CWC27 p.Ser89Pro (c.265T>C)?

CWC27 p.Ser89Pro (c.265T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CWC27 p.Ser89Pro (c.265T>C) in the general population?

CWC27 p.Ser89Pro (c.265T>C) is very rare (popmax 0.00551%, afr) (gnomAD).

What do computational predictors say about CWC27 p.Ser89Pro (c.265T>C)?

AlphaMissense predicts likely pathogenic (score 0.8105) — an in-silico prediction, not a clinical call.

CWC27 p.Ser89Pro

c.265T>C · rs138235746 · VCV1349899

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8105 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00551%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8105	likely pathogenic
REVEL	0.16	moderately benign-leaning
SaProt	LLR -9.97	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 5.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 249 kb · p 0.12 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00551% African / African-American · 4/72,644 alleles

Filtering AF 0.00179% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00107%

Overall 0.000317% 5/1,576,556 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00551%	18,161
Admixed American	0.0019%	52,558

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.Ser89Pro
Coding: c.265T>C
MANE Select: NM_005869
dbSNP: rs138235746
Type: single nucleotide variant
Location: chr5:64783848 (GRCh38)
Gene constraint: LOEUF 1.181 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.93 · 9 PDB
Residue 89: the ppiase cyclophilin-type domain; a UniProt-annotated variant site (in rpska)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CWC27 c.1042+5G>A Uncertain significance ★★ same condition
CWC27 p.Ala102Thr Uncertain significance ★★ ⚠ same condition
CWC27 p.Ala267Thr Uncertain significance ★★ ⚠ same condition
CWC27 p.Arg119Gln Uncertain significance ★★ ⚠ same condition
CWC27 p.Arg282Thr Uncertain significance ★★ ⚠ same condition
CWC27 p.Arg325Gln Uncertain significance ★★ ⚠ same condition
CWC27 p.Arg325Trp Uncertain significance ★★ ⚠ same condition
CWC27 p.Arg361Gly Uncertain significance ★★ ⚠ same condition

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-ser89pro (accessed [today's date]).

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