Is CWC27 p.Pro256Ala (c.766C>G) pathogenic?

CWC27 p.Pro256Ala (c.766C>G) is classified Benign in CWC27 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0478); Common (popmax 46.5%, eas) — too common for a highly-penetrant pathogenic allele; Associated with metaphyseal chondrodysplasia-retinitis pigmentosa syndrome.

What condition is associated with CWC27 p.Pro256Ala (c.766C>G)?

CWC27 p.Pro256Ala (c.766C>G) is associated with metaphyseal chondrodysplasia-retinitis pigmentosa syndrome (ClinVar).

What do computational predictors say about CWC27 p.Pro256Ala (c.766C>G)?

AlphaMissense predicts likely benign (score 0.0478) — an in-silico prediction, not a clinical call.

CWC27 p.Pro256Ala

Q: How common is CWC27 p.Pro256Ala (c.766C>G) in the general population?

CWC27 p.Pro256Ala (c.766C>G) is common (popmax 46.5%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.766C>G · rs7735338 · VCV1167008

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0478 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 46.5%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

metaphyseal chondrodysplasia-retinitis pigmentosa syndrome

Computational evidence

Protein change
AlphaMissense	0.0478	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -5.09	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 1.4	GERP -3.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 249 kb · p 0.12 · regional, not allelic
Overall
CADD	0.153	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 46.5% East Asian · 15,825/34,060 alleles

Filtering AF 45.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 45.6%

Overall 28.5% 360,672/1,263,708 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	46.5%	2
African / African-American	44.9%	2
South Asian	36.2%	3
Finnishnot grpmax-eligible	32.4%	3
Remaining individualsnot grpmax-eligible	29%	3
European (non-Finnish)	26.6%	4
Ashkenazi Jewishnot grpmax-eligible	23.2%	4
Middle Eastern	23%	4
Amishnot grpmax-eligible	21.9%	5
Admixed American	17%	6

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.Pro256Ala
Coding: c.766C>G
MANE Select: NM_005869
dbSNP: rs7735338
Type: single nucleotide variant
Location: chr5:64801318 (GRCh38)
Gene constraint: LOEUF 1.181 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.93 · 9 PDB
Residue 256: a UniProt-annotated variant site (in rpska); a UniProt-annotated variant site (in); the 'disordered' region

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

Disease context

metaphyseal chondrodysplasia-retinitis pigmentosa syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CWC27 c.397-1G>A Likely pathogenic ★★ same condition
CWC27 c.938+2T>C Likely pathogenic ★★ same condition
CWC27 p.Arg143Ter Pathogenic/Likely pathogenic ★★ same condition
CWC27 p.Glu165= Pathogenic ★★ same condition
CWC27 p.Glu336Lys Uncertain significance ★★ ⚠ same condition
CWC27 p.Val335Gly Uncertain significance ★★ ⚠ same condition
CWC27 c.749+16G>T Benign ★★ same condition
CWC27 c.-31G>A Benign ★★ 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-pro256ala (accessed [today's date]).

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