Is WRAP53 p.Val508Ile (c.1522G>A) pathogenic?

WRAP53 p.Val508Ile (c.1522G>A) is classified Uncertain significance in WRAP53 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-03). AlphaMissense: likely benign (0.072); Ultra-rare (popmax 0.0151%, nfe); Associated with dyskeratosis congenita, autosomal recessive 3.

What condition is associated with WRAP53 p.Val508Ile (c.1522G>A)?

WRAP53 p.Val508Ile (c.1522G>A) is associated with dyskeratosis congenita, autosomal recessive 3 (ClinVar).

How common is WRAP53 p.Val508Ile (c.1522G>A) in the general population?

WRAP53 p.Val508Ile (c.1522G>A) is ultra-rare (popmax 0.0151%, nfe) (gnomAD).

How is Dyskeratosis congenita inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about WRAP53 p.Val508Ile (c.1522G>A)?

AlphaMissense predicts likely benign (score 0.072) — an in-silico prediction, not a clinical call.

WRAP53 p.Val508Ile

c.1522G>A · rs768089496 · VCV940521

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.072 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0151%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dyskeratosis congenita, autosomal recessive 3

Computational evidence

Protein change
AlphaMissense	0.072	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -7.31	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 0.91	GERP -4.8, phastCons 0.004
Regional constraint	o/e 1.32	unconstrained · MANE · 182 bp · p 0.0044 · regional, not allelic
Overall
CADD	6.203	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 0.0151% European (non-Finnish) · 178/1,180,002 alleles

Filtering AF 0.0132% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0125%

Overall 0.0118% 191/1,613,874 alleles · ultra-rare exomes 182/1,461,878 · genomes 9/151,996 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0151%	6,629
African / African-American	0.00935%	10,692
Remaining individualsnot grpmax-eligible	0.008%	12,496
Admixed American	0.00167%	59,988

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.Val508Ile
Coding: c.1522G>A
MANE Select: NM_001143992
dbSNP: rs768089496
Type: single nucleotide variant
Location: chr17:7703361 (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 508: a β-strand

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

Disease context

dyskeratosis congenita, autosomal recessive 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Dyskeratosis congenita (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

WRAP53 p.Val508Leu Uncertain significance ★ ⚠ same residue
WRAP53 p.Val508= Likely benign ★ same residue
WRAP53 p.Arg265Gln Uncertain significance ★★ ⚠ same condition
WRAP53 p.Arg298Gln Uncertain significance ★★ ⚠ same condition
WRAP53 p.Arg298Trp Uncertain significance ★★ same condition
WRAP53 p.Arg307Trp Uncertain significance ★★ ⚠ same condition
WRAP53 p.Arg483His Uncertain significance ★★ ⚠ same condition
WRAP53 p.Arg506Cys Uncertain significance ★★ ⚠ same condition

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-val508ile (accessed [today's date]).

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