Is RECQL p.Pro535Ser (c.1603C>T) pathogenic?

RECQL p.Pro535Ser (c.1603C>T) is classified Uncertain significance in RECQL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-25). AlphaMissense: likely benign (0.3372); Very rare (popmax 8.48e-05%, nfe).

How common is RECQL p.Pro535Ser (c.1603C>T) in the general population?

RECQL p.Pro535Ser (c.1603C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about RECQL p.Pro535Ser (c.1603C>T)?

AlphaMissense predicts likely benign (score 0.3372) — an in-silico prediction, not a clinical call.

RECQL p.Pro535Ser

c.1603C>T · rs2137316099 · VCV3222942

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3372 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3372	likely benign
REVEL	0.11	moderately benign-leaning
SaProt	LLR -7.06	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 29 kb · p 0.095 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 8.48e-05% European (non-Finnish) · 1/1,179,434 alleles

Overall 6.2e-05% 1/1,613,150 alleles · very rare exomes 1/1,461,006 · genomes 0/152,144 · 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.Pro535Ser
Coding: c.1603C>T
MANE Select: NM_002907
dbSNP: rs2137316099
Type: single nucleotide variant
Location: chr12:21471492 (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 535: 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.Pro535Leu Uncertain significance ★★ same residue
RECQL p.Pro535Arg Uncertain significance ★ ⚠ same residue
RECQL p.Pro535His Uncertain significance ★ ⚠ same residue
RECQL p.Pro535Thr Uncertain significance ★ ⚠ same residue
RECQL p.Pro535= Likely benign ★ same residue
RECQL p.Pro535fs Uncertain significance ★ same residue
RECQL c.1098+1G>A Uncertain significance ★★ same type
RECQL c.1216+3A>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-pro535ser (accessed [today's date]).

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