Is WRAP53 p.His255Arg (c.764A>G) pathogenic?

WRAP53 p.His255Arg (c.764A>G) is classified Uncertain significance in WRAP53 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-06). AlphaMissense: ambiguous (0.5011); Very rare (popmax 0.0078%, nfe); Associated with dyskeratosis congenita.

What condition is associated with WRAP53 p.His255Arg (c.764A>G)?

WRAP53 p.His255Arg (c.764A>G) is associated with dyskeratosis congenita (ClinVar).

How common is WRAP53 p.His255Arg (c.764A>G) in the general population?

WRAP53 p.His255Arg (c.764A>G) is very rare (popmax 0.0078%, 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.His255Arg (c.764A>G)?

AlphaMissense predicts ambiguous (score 0.5011) — an in-silico prediction, not a clinical call.

WRAP53 p.His255Arg

c.764A>G · rs375474753 · VCV2173011

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5011 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0078%, nfe)

Conditions

dyskeratosis congenita

Computational evidence

Protein change
AlphaMissense	0.5011	ambiguous
REVEL	0.351	indeterminate
SaProt	LLR -9.51	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 14 kb · p 0.54 · regional, not allelic
Overall
CADD	26.3	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 0.0078% European (non-Finnish) · 92/1,180,044 alleles

Filtering AF 0.00647% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.006%

Overall 0.00576% 93/1,614,070 alleles · very rare exomes 92/1,461,892 · genomes 1/152,178 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0078%	12,827
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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.His255Arg
Coding: c.764A>G
MANE Select: NM_001143992
dbSNP: rs375474753
Type: single nucleotide variant
Location: chr17:7701491 (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 255: a β-strand

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

Disease context

dyskeratosis congenita — 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.His255= Likely benign ★★ same residue
WRAP53 p.Arg265Gln Uncertain significance ★★ ⚠ same condition
WRAP53 p.Arg298Gln Uncertain significance ★★ ⚠ same condition
WRAP53 p.Arg298Gly Uncertain significance ★★ ⚠ same condition
WRAP53 p.Arg301Cys Uncertain significance ★★ ⚠ same condition
WRAP53 p.Arg409Leu 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-his255arg (accessed [today's date]).

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