Is WRAP53 p.Ala522fs (c.1565del) pathogenic?

WRAP53 p.Ala522fs (c.1565del) is classified Uncertain significance in WRAP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-05). Ultra-rare (popmax 0.0107%, afr).

How common is WRAP53 p.Ala522fs (c.1565del) in the general population?

WRAP53 p.Ala522fs (c.1565del) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

WRAP53 p.Ala522fs

c.1565del · rs373064567 · VCV1427776

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (11 of 11) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.18	GERP -5.1
Overall
CADD	14.49	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0107% African / African-American · 8/74,704 alleles

Filtering AF 0.00529% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00409% 66/1,611,876 alleles · ultra-rare exomes 61/1,459,818 · genomes 5/152,058 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,338
South Asian	0.0088%	11,369
European (non-Finnish)	0.00407%	24,558
East Asian	0.00224%	44,622
Remaining individualsnot grpmax-eligible	0.0016%	62,390

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.Ala522fs
Coding: c.1565del
MANE Select: NM_001143992
dbSNP: rs373064567
Type: Deletion
Location: chr17:7703404 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 73.96 · 7 PDB
Residue 522: a UniProt-annotated variant site (in)

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

Similar variants

WRAP53 p.Ala522Arg Uncertain significance ★ same residue
WRAP53 p.Ala522Thr Uncertain significance ★ ⚠ same residue
WRAP53 p.Ala522Trp Uncertain significance ★ same residue
WRAP53 p.Ala522Val Uncertain significance ★ ⚠ same residue
WRAP53 p.Ala522= Likely benign ★ same residue
WRAP53 p.Ala522Gly Benign ★ same residue
WRAP53 p.Gln7fs Uncertain significance ★★ same type
WRAP53 p.Gly350fs 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-ala522fs (accessed [today's date]).

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