Is WRAP53 p.Met129Val (c.385A>G) pathogenic?

WRAP53 p.Met129Val (c.385A>G) is classified Likely benign in WRAP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-20). AlphaMissense: likely benign (0.0553); Ultra-rare (popmax 0.0329%, mid); Associated with dyskeratosis congenita.

What condition is associated with WRAP53 p.Met129Val (c.385A>G)?

WRAP53 p.Met129Val (c.385A>G) is associated with dyskeratosis congenita (ClinVar).

How common is WRAP53 p.Met129Val (c.385A>G) in the general population?

WRAP53 p.Met129Val (c.385A>G) is ultra-rare (popmax 0.0329%, mid) (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.Met129Val (c.385A>G)?

AlphaMissense predicts likely benign (score 0.0553) — an in-silico prediction, not a clinical call.

WRAP53 p.Met129Val

c.385A>G · VCV3982351

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0553 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dyskeratosis congenita

Computational evidence

Protein change
AlphaMissense	0.0553	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -4.96	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 -2.6	GERP -5.2
Regional constraint	o/e 0.97	unconstrained · MANE · 14 kb · p 0.54 · regional, not allelic
Overall
CADD	0.002	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00031% 5/1,614,082 alleles · ultra-rare exomes 3/1,461,874 · genomes 2/152,208 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
Remaining individualsnot grpmax-eligible	0.0032%	31,245
European (non-Finnish)	8.47e-05%	1,180,050

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.Met129Val
Coding: c.385A>G
MANE Select: NM_001143992
Type: single nucleotide variant
Location: chr17:7689033 (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 129: the 'disordered' region

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-met129val (accessed [today's date]).

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