Is CWC22 p.Asp741Val (c.2222A>T) pathogenic?

CWC22 p.Asp741Val (c.2222A>T) is classified Benign in CWC22 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-02-25). AlphaMissense: likely benign (0.0948); Common (popmax 6.52%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CWC22 p.Asp741Val (c.2222A>T)?

AlphaMissense predicts likely benign (score 0.0948) — an in-silico prediction, not a clinical call.

CWC22 p.Asp741Val

Q: How common is CWC22 p.Asp741Val (c.2222A>T) in the general population?

CWC22 p.Asp741Val (c.2222A>T) is common (popmax 6.52%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2222A>T · rs11903115 · VCV709625

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0948 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.52%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0948	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -7.29	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 6.2	GERP 2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 5,577 bp · p 0.59 · regional, not allelic
Overall
CADD	22.9	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 6.52% African / African-American · 4,890/75,002 alleles

Filtering AF 6.37% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.3%

Overall 0.352% 5,683/1,612,638 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.52%	15
Remaining individualsnot grpmax-eligible	0.476%	210
Admixed American	0.432%	232
Middle Eastern	0.363%	275
Ashkenazi Jewishnot grpmax-eligible	0.0845%	1,184
European (non-Finnish)	0.0153%	6,553
South Asian	0.011%	9,106

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: CWC22
Protein: p.Asp741Val
Coding: c.2222A>T
MANE Select: NM_020943
dbSNP: rs11903115
Type: single nucleotide variant
Location: chr2:179945634 (GRCh38)
Gene constraint: LOEUF 0.875 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.00 · 29 PDB
Residue 741: a UniProt-annotated variant site (in); the 'disordered' region

Full CWC22 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CWC22 p.Gln365= Benign ★★ same type
CWC22 p.Ala419Thr Uncertain significance ★ ⚠ same type
CWC22 p.Ala674Ser Uncertain significance ★ ⚠ same type
CWC22 p.Arg128Pro Uncertain significance ★ ⚠ same type
CWC22 p.Arg156Lys Uncertain significance ★ ⚠ same type
CWC22 p.Arg17Thr Uncertain significance ★ ⚠ same type
CWC22 p.Arg236Thr Uncertain significance ★ ⚠ same type
CWC22 p.Arg246Gln 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/cwc22-p-asp741val (accessed [today's date]).

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