Is CWC27 p.Ala356Pro (c.1066G>C) pathogenic?

CWC27 p.Ala356Pro (c.1066G>C) is classified Uncertain significance in CWC27 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-02-17). AlphaMissense: likely benign (0.2399); Very rare (popmax 0.00399%, nfe).

How common is CWC27 p.Ala356Pro (c.1066G>C) in the general population?

CWC27 p.Ala356Pro (c.1066G>C) is very rare (popmax 0.00399%, nfe) (gnomAD).

What do computational predictors say about CWC27 p.Ala356Pro (c.1066G>C)?

AlphaMissense predicts likely benign (score 0.2399) — an in-silico prediction, not a clinical call.

CWC27 p.Ala356Pro

c.1066G>C · rs751813292 · VCV1020212

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2399 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00399%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2399	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -8.29	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 5.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 249 kb · p 0.12 · regional, not allelic
Overall
CADD	21.2	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 0.00399% European (non-Finnish) · 47/1,178,162 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00305% 49/1,609,090 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00399%	25,067
Remaining individualsnot grpmax-eligible	0.00161%	62,272
African / African-American	0.00134%	74,366

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.Ala356Pro
Coding: c.1066G>C
MANE Select: NM_005869
dbSNP: rs751813292
Type: single nucleotide variant
Location: chr5:64971726 (GRCh38)
Gene constraint: LOEUF 1.181 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.93 · 9 PDB
Residue 356: a UniProt-annotated variant site (in rpska); the 'disordered' region

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

Similar variants

CWC27 p.Ala356fs Pathogenic ★★ same residue
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

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-ala356pro (accessed [today's date]).

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