Is WRAP53 p.His376Pro (c.1127A>C) pathogenic?

WRAP53 p.His376Pro (c.1127A>C) is classified Uncertain significance in WRAP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-10-08). AlphaMissense: ambiguous (0.3947); Very rare (popmax 0.00668%, afr).

How common is WRAP53 p.His376Pro (c.1127A>C) in the general population?

WRAP53 p.His376Pro (c.1127A>C) is very rare (popmax 0.00668%, afr) (gnomAD).

What do computational predictors say about WRAP53 p.His376Pro (c.1127A>C)?

AlphaMissense predicts ambiguous (score 0.3947) — an in-silico prediction, not a clinical call.

WRAP53 p.His376Pro

c.1127A>C · rs375249946 · VCV1055122

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3947 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, afr)

Computational evidence

Protein change
AlphaMissense	0.3947	ambiguous
REVEL	0.418	indeterminate
SaProt	LLR -10.78	damaging
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 0.73	unconstrained · MANE · 932 bp · p 8.6e-05 · regional, not allelic
Overall
CADD	24.1	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 0.00668% African / African-American · 5/74,882 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.00031% 5/1,612,678 alleles · very rare exomes 1/1,460,612 · genomes 4/152,066 · joint denominator

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.His376Pro
Coding: c.1127A>C
MANE Select: NM_001143992
dbSNP: rs375249946
Type: single nucleotide variant
Location: chr17:7702515 (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 376: a UniProt-annotated variant site (in dkcb3; shortened telomeres; disrupts telomerase localization to cajal bodies resulting in misdirection of telomerase rna to nucleoli)

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

Similar variants

WRAP53 p.His376Tyr Pathogenic ⚠ 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-his376pro (accessed [today's date]).

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