Is WRAP53 p.Val454fs (c.1359del) pathogenic?

WRAP53 p.Val454fs (c.1359del) is classified Uncertain significance in WRAP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-13). Very rare (popmax 0.000593%, nfe).

How common is WRAP53 p.Val454fs (c.1359del) in the general population?

WRAP53 p.Val454fs (c.1359del) is very rare (popmax 0.000593%, nfe) (gnomAD).

WRAP53 p.Val454fs

c.1359del · rs1567580888 · VCV1438172

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

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 within the last 50 nt of the penultimate exon (10 of 11, 46 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.97	GERP -1.9, phastCons 1
Overall
CADD	22.0	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 0.000593% European (non-Finnish) · 7/1,180,038 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,614,014 alleles · very rare exomes 7/1,461,838 · genomes 1/152,176 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)grpmax	0.000593%	168,577

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val454fs
Coding: c.1359del
MANE Select: NM_001143992
dbSNP: rs1567580888
Type: Deletion
Location: chr17:7703081 (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 454: a β-strand

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

Similar variants

WRAP53 p.Val454Leu Uncertain significance ★ ⚠ same residue
WRAP53 p.Val454Met Uncertain significance ★ ⚠ same residue
WRAP53 p.Val454= Likely benign ★ same residue
WRAP53 p.Gln7fs Uncertain significance ★★ same type
WRAP53 p.Gly350fs Uncertain significance ★★ same type
WRAP53 p.Leu373fs Pathogenic ★ same type
WRAP53 p.Ser456fs Likely pathogenic ★ same type
WRAP53 c.731+3_731+4del 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-val454fs (accessed [today's date]).

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