Is WRAP53 p.Cys519Trp (c.1557T>G) pathogenic?

WRAP53 p.Cys519Trp (c.1557T>G) is classified Uncertain significance in WRAP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-24). AlphaMissense: likely pathogenic (0.6538); Very rare (popmax 0.0011%, sas).

How common is WRAP53 p.Cys519Trp (c.1557T>G) in the general population?

WRAP53 p.Cys519Trp (c.1557T>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about WRAP53 p.Cys519Trp (c.1557T>G)?

AlphaMissense predicts likely pathogenic (score 0.6538) — an in-silico prediction, not a clinical call.

WRAP53 p.Cys519Trp

c.1557T>G · VCV4883467

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6538 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6538	likely pathogenic
REVEL	0.187	benign-leaning
SaProt	LLR -8.09	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.33, phastCons 1
Regional constraint	o/e 1.32	unconstrained · MANE · 182 bp · p 0.0044 · regional, not allelic
Overall
CADD	23.5	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 0.0011% South Asian · 1/90,658 alleles

Overall 0.000124% 2/1,607,406 alleles · very rare exomes 2/1,457,342 · genomes 0/150,064 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,658
European (non-Finnish)	8.5e-05%	1,177,067

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: WRAP53
Protein: p.Cys519Trp
Coding: c.1557T>G
MANE Select: NM_001143992
Type: single nucleotide variant
Location: chr17:7703396 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 73.96 · 7 PDB

Full WRAP53 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

WRAP53 p.Cys519_Gly520delinsTrp Uncertain significance ★ same residue
WRAP53 c.823-3C>T Uncertain significance ★★ same type
WRAP53 p.Ala118Thr Uncertain significance ★★ ⚠ same type
WRAP53 p.Arg265Gln Uncertain significance ★★ ⚠ same type
WRAP53 p.Arg298Gln Uncertain significance ★★ ⚠ same type
WRAP53 p.Arg298Gly Uncertain significance ★★ ⚠ same type
WRAP53 p.Arg298Trp Uncertain significance ★★ same type
WRAP53 p.Arg301Cys 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/wrap53-p-cys519trp (accessed [today's date]).

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