Is RECQL4 p.Pro466Ser (c.1396C>T) pathogenic?

RECQL4 p.Pro466Ser (c.1396C>T) is classified Uncertain significance in RECQL4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-06). AlphaMissense: ambiguous (0.3629); Ultra-rare (popmax 0.0331%, mid); Associated with Baller-Gerold syndrome.

What condition is associated with RECQL4 p.Pro466Ser (c.1396C>T)?

RECQL4 p.Pro466Ser (c.1396C>T) is associated with Baller-Gerold syndrome (ClinVar).

How common is RECQL4 p.Pro466Ser (c.1396C>T) in the general population?

RECQL4 p.Pro466Ser (c.1396C>T) is ultra-rare (popmax 0.0331%, mid) (gnomAD).

What do computational predictors say about RECQL4 p.Pro466Ser (c.1396C>T)?

AlphaMissense predicts ambiguous (score 0.3629) — an in-silico prediction, not a clinical call.

RECQL4 p.Pro466Ser

c.1396C>T · rs562809072 · VCV459323

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3629 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0331%, mid)

Conditions

Baller-Gerold syndrome

Computational evidence

Protein change
AlphaMissense	0.3629	ambiguous
SaProt	LLR -10.97	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.39	unconstrained · MANE · 6,350 bp · p 1.8e-56 · regional, not allelic
Overall
CADD	19.88	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; SaProt is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0331% Middle Eastern · 2/6,038 alleles

Filtering AF 0.00584% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00243%

Overall 0.00044% 7/1,590,572 alleles · ultra-rare exomes 7/1,438,224 · genomes 0/152,348 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0331%	3,019
South Asian	0.00114%	87,980
European (non-Finnish)	0.000342%	292,319

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.Pro466Ser
Coding: c.1396C>T
MANE Select: NM_004260
dbSNP: rs562809072
Type: single nucleotide variant
Location: chr8:144515237 (GRCh38)
Gene constraint: LOEUF 1.519 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.32 · 2 PDB
Residue 466: 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

Similar variants

RECQL4 p.Pro466Ala Uncertain significance ★★ ⚠ same residue
RECQL4 p.Pro466= Benign/Likely benign ★★ same residue
RECQL4 p.Pro466Leu Conflicting classifications of pathogenicity ★ 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
RECQL4 c.1704+2T>G 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-pro466ser (accessed [today's date]).

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