Is RECQL4 p.Pro103Leu (c.308C>T) pathogenic?

RECQL4 p.Pro103Leu (c.308C>T) is classified Conflicting classifications of pathogenicity in RECQL4 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0894); Rare (popmax 0.147%, nfe); Associated with Rothmund-Thomson syndrome type 2.

What condition is associated with RECQL4 p.Pro103Leu (c.308C>T)?

RECQL4 p.Pro103Leu (c.308C>T) is associated with Rothmund-Thomson syndrome type 2, Baller-Gerold syndrome, hereditary neoplastic syndrome (ClinVar).

How common is RECQL4 p.Pro103Leu (c.308C>T) in the general population?

RECQL4 p.Pro103Leu (c.308C>T) is rare (popmax 0.147%, nfe) (gnomAD).

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.Pro103Leu (c.308C>T)?

AlphaMissense predicts likely benign (score 0.0894) — an in-silico prediction, not a clinical call.

RECQL4 p.Pro103Leu

c.308C>T · rs199543866 · VCV239755

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0894 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.147%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Conditions

Rothmund-Thomson syndrome type 2

Computational evidence

Protein change
AlphaMissense	0.0894	likely benign
SaProt	LLR -6.25	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 -0.71	GERP -2.8
Regional constraint	o/e 1.39	unconstrained · MANE · 6,350 bp · p 1.8e-56 · regional, not allelic
Overall
CADD	1.354	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 0.147% European (non-Finnish) · 1,736/1,179,758 alleles

Filtering AF 0.141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.139%

Overall 0.115% 1,853/1,612,326 alleles · rare exomes 1,735/1,460,058 · genomes 118/152,268 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.147%	680
Remaining individualsnot grpmax-eligible	0.103%	975
African / African-American	0.0427%	2,342
Admixed American	0.0233%	4,285
Finnishnot grpmax-eligible	0.0112%	8,949

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.Pro103Leu
Coding: c.308C>T
MANE Select: NM_004260
dbSNP: rs199543866
Type: single nucleotide variant
Location: chr8:144517096 (GRCh38)
Gene constraint: LOEUF 1.519 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.32 · 2 PDB
Residue 103: 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 hereditary neoplastic syndrome

For Rothmund-Thomson syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

RECQL4 p.Pro103Ala Uncertain significance ★★ ⚠ same residue
RECQL4 p.Pro103Ser Uncertain significance ★★ ⚠ same residue
RECQL4 p.Pro103= 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-pro103leu (accessed [today's date]).

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