Is RECQL p.Ala459= (c.1377T>C) pathogenic?

RECQL p.Ala459= (c.1377T>C) is classified Likely benign in RECQL (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-21). Very rare (popmax 0.00133%, afr).

How common is RECQL p.Ala459= (c.1377T>C) in the general population?

RECQL p.Ala459= (c.1377T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

RECQL p.Ala459=

c.1377T>C · rs2540334683 · VCV1771201

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.61	GERP -2.6, phastCons 0.94
Overall
CADD	7.258	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,002 alleles

Overall 6.2e-05% 1/1,612,830 alleles · very rare exomes 1/1,460,602 · genomes 0/152,228 · 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: RECQL
Protein: p.Ala459=
Coding: c.1377T>C
MANE Select: NM_002907
dbSNP: rs2540334683
Type: single nucleotide variant
Location: chr12:21473621 (GRCh38)
Gene constraint: LOEUF 1.235 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.55 · 7 PDB
Residue 459: a UniProt-annotated variant site (in recon; likely pathogenic; reduces dna helicase activity on a forked duplex dna substrate; decreases atpase activity; reduces dna-binding; defect in repairing abortive top1/topoisomerase 1 and top2/topoisomerase 2 cleavage complexes; failure to efficiently restart replication following exposure to genotoxins, such as hydroxyurea (hu) and methyl methane sulfonate (mms); no impact on nuclear localization and interaction with parp1; no effect on capacity to promote single-strand dna annealing); an α-helix

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

Similar variants

RECQL p.Ala459Ser Uncertain significance ★★ ⚠ same residue
RECQL p.Ala459Pro Uncertain significance ★ ⚠ same residue
RECQL p.Ala459Thr Uncertain significance ★ ⚠ same residue
RECQL c.1098+1G>A Uncertain significance ★★ same type
RECQL c.1216+3A>G Uncertain significance ★★ same type
RECQL c.1217-3C>T Uncertain significance ★★ same type
RECQL c.1355+1G>A Uncertain significance ★★ same type
RECQL c.1356-12A>G 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/recql-p-ala459 (accessed [today's date]).

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