Is RECQL4 p.Pro222Ser (c.664C>T) pathogenic?

RECQL4 p.Pro222Ser (c.664C>T) is classified Conflicting classifications of pathogenicity in RECQL4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-03-16). AlphaMissense: likely benign (0.0687); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with RECQL4 p.Pro222Ser (c.664C>T)?

RECQL4 p.Pro222Ser (c.664C>T) is associated with Inborn genetic diseases, Baller-Gerold syndrome (ClinVar).

How common is RECQL4 p.Pro222Ser (c.664C>T) in the general population?

RECQL4 p.Pro222Ser (c.664C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about RECQL4 p.Pro222Ser (c.664C>T)?

AlphaMissense predicts likely benign (score 0.0687) — an in-silico prediction, not a clinical call.

RECQL4 p.Pro222Ser

c.664C>T · rs758876038 · VCV239781

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0687 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0687	likely benign
SaProt	LLR -6.80	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.78	GERP -3
Regional constraint	o/e 1.39	unconstrained · MANE · 6,350 bp · p 1.8e-56 · regional, not allelic
Overall
CADD	0.004	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 0.00223% East Asian · 1/44,882 alleles

Overall 0.000186% 3/1,608,664 alleles · very rare exomes 3/1,456,312 · genomes 0/152,352 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,882
South Asian	0.0011%	91,014
European (non-Finnish)	8.48e-05%	1,179,768

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.Pro222Ser
Coding: c.664C>T
MANE Select: NM_004260
dbSNP: rs758876038
Type: single nucleotide variant
Location: chr8:144516455 (GRCh38)
Gene constraint: LOEUF 1.519 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.32 · 2 PDB
Residue 222: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Baller-Gerold syndrome

Similar variants

RECQL4 p.Pro222Arg Uncertain significance ★★ ⚠ same residue
RECQL4 p.Pro222Leu Uncertain significance ★★ ⚠ same residue
RECQL4 p.Pro222= 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
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-pro222ser (accessed [today's date]).

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