Is ALYREF p.Gln253Glu (c.757C>G) pathogenic?

ALYREF p.Gln253Glu (c.757C>G) is classified Uncertain significance in ALYREF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-30). Very rare (popmax 0.00223%, eas).

How common is ALYREF p.Gln253Glu (c.757C>G) in the general population?

ALYREF p.Gln253Glu (c.757C>G) is very rare (popmax 0.00223%, eas) (gnomAD).

ALYREF p.Gln253Glu

c.757C>G · VCV4045802

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.257	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 422 bp · p 0.81 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,824 alleles

Overall 6.86e-05% 1/1,458,372 alleles · very rare

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: ALYREF
Protein: p.Gln253Glu
Coding: c.757C>G
MANE Select: NM_005782
Type: single nucleotide variant
Location: chr17:81888264 (GRCh38)
Gene constraint: LOEUF 0.235 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.65 · 4 PDB
Residue 253: the 'disordered' region

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

Similar variants

ALYREF p.Pro2His Uncertain significance ★ same type
ALYREF p.Ser4Phe Uncertain significance ★ same type
ALYREF p.Ser201= Likely benign ★ same type
ALYREF p.Arg231Leu Uncertain significance same type
ALYREF p.Leu16= Likely benign 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/alyref-p-gln253glu (accessed [today's date]).

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