Is WRAP53 p.Leu157Phe (c.469C>T) pathogenic?

WRAP53 p.Leu157Phe (c.469C>T) is classified Uncertain significance in WRAP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-07). AlphaMissense: likely benign (0.188); Very rare (popmax 0.00678%, nfe).

How common is WRAP53 p.Leu157Phe (c.469C>T) in the general population?

WRAP53 p.Leu157Phe (c.469C>T) is very rare (popmax 0.00678%, nfe) (gnomAD).

What do computational predictors say about WRAP53 p.Leu157Phe (c.469C>T)?

AlphaMissense predicts likely benign (score 0.188) — an in-silico prediction, not a clinical call.

WRAP53 p.Leu157Phe

c.469C>T · rs746794861 · VCV1419086

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.188 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00678%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.188	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -5.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.7	GERP 1.3, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 14 kb · p 0.54 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00678% European (non-Finnish) · 80/1,180,042 alleles

Filtering AF 0.00554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.00514% 83/1,613,996 alleles · very rare exomes 81/1,461,892 · genomes 2/152,104 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00678%	14,751
African / African-American	0.00267%	37,443
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Leu157Phe
Coding: c.469C>T
MANE Select: NM_001143992
dbSNP: rs746794861
Type: single nucleotide variant
Location: chr17:7689261 (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 157: a β-strand

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

Similar variants

WRAP53 p.Leu157= Likely benign ★★ 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-leu157phe (accessed [today's date]).

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