Is CWC27 p.Leu289Phe (c.867A>T) pathogenic?

CWC27 p.Leu289Phe (c.867A>T) is classified Uncertain significance in CWC27 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-08-30). AlphaMissense: ambiguous (0.4922); Ultra-rare (popmax 0.0217%, amr); Associated with Inborn genetic diseases.

What condition is associated with CWC27 p.Leu289Phe (c.867A>T)?

CWC27 p.Leu289Phe (c.867A>T) is associated with Inborn genetic diseases, inherited retinal dystrophy (ClinVar).

How common is CWC27 p.Leu289Phe (c.867A>T) in the general population?

CWC27 p.Leu289Phe (c.867A>T) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about CWC27 p.Leu289Phe (c.867A>T)?

AlphaMissense predicts ambiguous (score 0.4922) — an in-silico prediction, not a clinical call.

CWC27 p.Leu289Phe

c.867A>T · rs140234898 · VCV846487

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4922 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4922	ambiguous
REVEL	0.203	benign-leaning
SaProt	LLR -8.40	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -0.52, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 249 kb · p 0.12 · regional, not allelic
Overall
CADD	21.5	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 0.0217% Admixed American · 13/59,868 alleles

Filtering AF 0.0128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.0067% 108/1,612,678 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,605
Middle Eastern	0.0166%	6,008
European (non-Finnish)	0.00738%	13,556
Remaining individualsnot grpmax-eligible	0.00641%	15,602
African / African-American	0.00401%	24,950

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.Leu289Phe
Coding: c.867A>T
MANE Select: NM_005869
dbSNP: rs140234898
Type: single nucleotide variant
Location: chr5:64804315 (GRCh38)
Gene constraint: LOEUF 1.181 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.93 · 9 PDB
Residue 289: a UniProt-annotated variant site (in rpska); the 'disordered' region

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

Also linked: inherited retinal dystrophy

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-leu289phe (accessed [today's date]).

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