Is RECQL p.Arg539Pro (c.1616G>C) pathogenic?

RECQL p.Arg539Pro (c.1616G>C) is classified Uncertain significance in RECQL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-06). AlphaMissense: likely pathogenic (0.9294); Very rare (popmax 0.00167%, amr).

How common is RECQL p.Arg539Pro (c.1616G>C) in the general population?

RECQL p.Arg539Pro (c.1616G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about RECQL p.Arg539Pro (c.1616G>C)?

AlphaMissense predicts likely pathogenic (score 0.9294) — an in-silico prediction, not a clinical call.

RECQL p.Arg539Pro

c.1616G>C · rs367657766 · VCV1254239

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9294 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9294	likely pathogenic
REVEL	0.347	indeterminate
SaProt	LLR -14.63	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.22	GERP 2, phastCons 0.007
Regional constraint	o/e 0.94	unconstrained · MANE · 29 kb · p 0.095 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,874 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000992% 16/1,613,020 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,874
African / African-American	0.00134%	74,850
European (non-Finnish)	0.00119%	84,243

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.Arg539Pro
Coding: c.1616G>C
MANE Select: NM_002907
dbSNP: rs367657766
Type: single nucleotide variant
Location: chr12:21471479 (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 539: the 'winged-helix domain' region; an α-helix

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

Similar variants

RECQL p.Arg539Cys Uncertain significance ★★ ⚠ same residue
RECQL p.Arg539His Uncertain significance ★★ same residue
RECQL p.Arg539Leu 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-arg539pro (accessed [today's date]).

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