Is RECQL4 p.Ser92Pro (c.274T>C) pathogenic?

RECQL4 p.Ser92Pro (c.274T>C) is classified Benign in RECQL4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0454); Common (popmax 100%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with Rothmund-Thomson syndrome type 2.

What condition is associated with RECQL4 p.Ser92Pro (c.274T>C)?

RECQL4 p.Ser92Pro (c.274T>C) is associated with Rothmund-Thomson syndrome type 2, Baller-Gerold syndrome, rapadilino syndrome (ClinVar).

How is Rothmund-Thomson syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about RECQL4 p.Ser92Pro (c.274T>C)?

AlphaMissense predicts likely benign (score 0.0454) — an in-silico prediction, not a clinical call.

RECQL4 p.Ser92Pro

Q: How common is RECQL4 p.Ser92Pro (c.274T>C) in the general population?

RECQL4 p.Ser92Pro (c.274T>C) is common (popmax 100%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.274T>C · rs2721190 · VCV135161

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0454 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 100%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Conditions

Rothmund-Thomson syndrome type 2

Computational evidence

Protein change
AlphaMissense	0.0454	likely benign
SaProt	LLR -5.54	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 1.1	GERP -3.2, phastCons 0.15
Regional constraint	o/e 1.39	unconstrained · MANE · 6,350 bp · p 1.8e-56 · regional, not allelic
Overall
CADD	1.478	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 100% European (non-Finnish) · 1,179,312/1,179,722 alleles

Filtering AF 99.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 99.8%

Overall 98.9% 1,593,870/1,612,104 alleles · common exomes 1,444,084/1,459,726 · genomes 149,786/152,378 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	100%	1
Ashkenazi Jewishnot grpmax-eligible	100%	1
European (non-Finnish)grpmax	100%	1
South Asian	99.8%	1
Finnishnot grpmax-eligible	99.7%	1
Middle Eastern	99.6%	1
Remaining individualsnot grpmax-eligible	98.9%	1
African / African-American	98.4%	1
Admixed American	91.8%	1
East Asian	76.3%	1

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser92Pro
Coding: c.274T>C
MANE Select: NM_004260
dbSNP: rs2721190
Type: single nucleotide variant
Location: chr8:144517130 (GRCh38)
Gene constraint: LOEUF 1.519 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.32 · 2 PDB
Residue 92: a UniProt-annotated variant site (in); the 'disordered' region

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

Disease context

Rothmund-Thomson syndrome type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Baller-Gerold syndrome rapadilino syndrome

For Rothmund-Thomson syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

RECQL4 p.Ser92= Benign ★ same residue
RECQL4 p.Ser92Arg Uncertain significance ★ same residue
RECQL4 p.Ser92Leu Benign ★ same residue
RECQL4 p.Ser92Phe 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-ser92pro (accessed [today's date]).

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