Is WRAP53 p.Pro359Ser (c.1075C>T) pathogenic?

WRAP53 p.Pro359Ser (c.1075C>T) is classified Conflicting classifications of pathogenicity in WRAP53 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-24). AlphaMissense: likely benign (0.1275); Rare (popmax 0.308%, afr); Associated with dyskeratosis congenita.

What condition is associated with WRAP53 p.Pro359Ser (c.1075C>T)?

WRAP53 p.Pro359Ser (c.1075C>T) is associated with dyskeratosis congenita (ClinVar).

How common is WRAP53 p.Pro359Ser (c.1075C>T) in the general population?

WRAP53 p.Pro359Ser (c.1075C>T) is rare (popmax 0.308%, afr) (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.Pro359Ser (c.1075C>T)?

AlphaMissense predicts likely benign (score 0.1275) — an in-silico prediction, not a clinical call.

WRAP53 p.Pro359Ser

c.1075C>T · rs149359927 · VCV392640

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1275 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.308%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dyskeratosis congenita

Computational evidence

Protein change
AlphaMissense	0.1275	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -9.66	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 2.3	GERP 1.3, phastCons 0.027
Regional constraint	o/e 0.73	unconstrained · MANE · 932 bp · p 8.6e-05 · regional, not allelic
Overall
CADD	19.17	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 0.308% African / African-American · 231/75,042 alleles

Filtering AF 0.275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.263%

Overall 0.0169% 273/1,614,092 alleles · rare exomes 142/1,461,778 · genomes 131/152,314 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.308%	325
Middle Eastern	0.066%	1,514
Remaining individualsnot grpmax-eligible	0.04%	2,500
Admixed American	0.015%	6,668
South Asian	0.00329%	30,363
European (non-Finnish)	8.47e-05%	1,180,032

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.Pro359Ser
Coding: c.1075C>T
MANE Select: NM_001143992
dbSNP: rs149359927
Type: single nucleotide variant
Location: chr17:7702463 (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 359: 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.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
WRAP53 p.Arg52Trp 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-pro359ser (accessed [today's date]).

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