Is RECQL p.Pro126Ser (c.376C>T) pathogenic?

RECQL p.Pro126Ser (c.376C>T) is classified Uncertain significance in RECQL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-26). AlphaMissense: likely pathogenic (0.7006); Ultra-rare (popmax 0.0105%, nfe).

How common is RECQL p.Pro126Ser (c.376C>T) in the general population?

RECQL p.Pro126Ser (c.376C>T) is ultra-rare (popmax 0.0105%, nfe) (gnomAD).

What do computational predictors say about RECQL p.Pro126Ser (c.376C>T)?

AlphaMissense predicts likely pathogenic (score 0.7006) — an in-silico prediction, not a clinical call.

RECQL p.Pro126Ser

c.376C>T · rs376895551 · VCV942124

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7006 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0105%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7006	likely pathogenic
REVEL	0.863	moderately pathogenic-leaning
SaProt	LLR -10.66	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 29 kb · p 0.095 · regional, not allelic
Overall
CADD	27.1	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 0.0105% European (non-Finnish) · 124/1,177,548 alleles

Filtering AF 0.00893% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00844%

Overall 0.00776% 125/1,610,362 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0105%	9,496
Remaining individualsnot grpmax-eligible	0.0016%	62,328

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.Pro126Ser
Coding: c.376C>T
MANE Select: NM_002907
dbSNP: rs376895551
Type: single nucleotide variant
Location: chr12:21490217 (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 126: the helicase atp-binding domain; an α-helix

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

Similar variants

RECQL p.Pro126Leu Uncertain significance ★★ ⚠ same residue
RECQL p.Pro126Thr 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
RECQL c.1667+5G>C 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-pro126ser (accessed [today's date]).

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