Is RECQL4 p.Arg758Pro (c.2273G>C) pathogenic?

RECQL4 p.Arg758Pro (c.2273G>C) is classified Uncertain significance in RECQL4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-07). AlphaMissense: likely pathogenic (0.7176); Very rare (popmax 0.00167%, amr); Associated with Baller-Gerold syndrome.

What condition is associated with RECQL4 p.Arg758Pro (c.2273G>C)?

RECQL4 p.Arg758Pro (c.2273G>C) is associated with Baller-Gerold syndrome, Rothmund-Thomson syndrome type 2 (ClinVar).

How common is RECQL4 p.Arg758Pro (c.2273G>C) in the general population?

RECQL4 p.Arg758Pro (c.2273G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about RECQL4 p.Arg758Pro (c.2273G>C)?

AlphaMissense predicts likely pathogenic (score 0.7176) — an in-silico prediction, not a clinical call.

RECQL4 p.Arg758Pro

c.2273G>C · rs748416710 · VCV1036666

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7176 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt

Conditions

Baller-Gerold syndrome

Computational evidence

Protein change
AlphaMissense	0.7176	likely pathogenic
SaProt	LLR -15.18	damaging
⇒ AlphaMissense and SaProt both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.7	GERP -3.9
Regional constraint	o/e 1.39	unconstrained · MANE · 6,350 bp · p 1.8e-56 · regional, not allelic
Overall
CADD	2.878	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; SaProt is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,948 alleles

Overall 0.000124% 2/1,608,612 alleles · very rare exomes 0/1,456,344 · genomes 2/152,268 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,948
African / African-American	0.00133%	74,948

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: RECQL4
Protein: p.Arg758Pro
Coding: c.2273G>C
MANE Select: NM_004260
dbSNP: rs748416710
Type: single nucleotide variant
Location: chr8:144513408 (GRCh38)
Gene constraint: LOEUF 1.519 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.32 · 2 PDB
Residue 758: the helicase c-terminal domain; a UniProt-annotated variant site (in rts2); an α-helix

Full RECQL4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Baller-Gerold syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Rothmund-Thomson syndrome type 2

Similar variants

RECQL4 p.Arg758Ter Pathogenic/Likely pathogenic ★★ same residue
RECQL4 p.Arg758Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
RECQL4 p.Arg758Gly Uncertain significance ★ ⚠ same residue
RECQL4 p.Arg758= Likely benign ★ same residue
RECQL4 c.1132-1G>A Likely pathogenic ★★ same condition
RECQL4 c.1259-1G>A Pathogenic/Likely pathogenic ★★ same condition
RECQL4 c.1391-1G>A Pathogenic ★★ same condition
RECQL4 c.1704+1G>A Pathogenic/Likely pathogenic ★★ 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/recql4-p-arg758pro (accessed [today's date]).

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