Is CWC27 p.Val15Ile (c.43G>A) pathogenic?

CWC27 p.Val15Ile (c.43G>A) is classified Uncertain significance in CWC27 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-05). AlphaMissense: likely benign (0.1782); Ultra-rare (popmax 0.0237%, afr).

How common is CWC27 p.Val15Ile (c.43G>A) in the general population?

CWC27 p.Val15Ile (c.43G>A) is ultra-rare (popmax 0.0237%, afr) (gnomAD).

What do computational predictors say about CWC27 p.Val15Ile (c.43G>A)?

AlphaMissense predicts likely benign (score 0.1782) — an in-silico prediction, not a clinical call.

CWC27 p.Val15Ile

c.43G>A · rs376182212 · VCV1053548

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1782 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0237%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1782	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -9.62	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 12	GERP 5.3, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 249 kb · p 0.12 · regional, not allelic
Overall
CADD	29.7	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 0.0237% African / African-American · 17/71,760 alleles

Filtering AF 0.0151% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0123%

Overall 0.00149% 23/1,540,866 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0237%	4,221
Remaining individualsnot grpmax-eligible	0.00506%	19,771
Admixed American	0.002%	49,998
European (non-Finnish)	0.000175%	569,917

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.Val15Ile
Coding: c.43G>A
MANE Select: NM_005869
dbSNP: rs376182212
Type: single nucleotide variant
Location: chr5:64774691 (GRCh38)
Gene constraint: LOEUF 1.181 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.93 · 9 PDB
Residue 15: 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-val15ile (accessed [today's date]).

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