Is RECQL p.Ser394Phe (c.1181C>T) pathogenic?

RECQL p.Ser394Phe (c.1181C>T) is classified Uncertain significance in RECQL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-01). AlphaMissense: likely pathogenic (0.992); Very rare (popmax 0.0011%, sas).

How common is RECQL p.Ser394Phe (c.1181C>T) in the general population?

RECQL p.Ser394Phe (c.1181C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about RECQL p.Ser394Phe (c.1181C>T)?

AlphaMissense predicts likely pathogenic (score 0.992) — an in-silico prediction, not a clinical call.

RECQL p.Ser394Phe

c.1181C>T · rs775276234 · VCV1021276

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.992 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.992	likely pathogenic · top 5% in RECQL
REVEL	0.799	moderately pathogenic-leaning
SaProt	LLR -16.23	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 12	GERP 2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 29 kb · p 0.095 · regional, not allelic
Overall
CADD	33.0	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 0.0011% South Asian · 1/90,900 alleles

Overall 0.000124% 2/1,612,280 alleles · very rare exomes 2/1,460,252 · genomes 0/152,028 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,424
South Asiangrpmax	0.0011%	90,900

Remaining individuals 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: RECQL
Protein: p.Ser394Phe
Coding: c.1181C>T
MANE Select: NM_002907
dbSNP: rs775276234
Type: single nucleotide variant
Location: chr12:21475503 (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 394: the helicase c-terminal domain

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

Similar variants

RECQL p.Ser394Cys Uncertain significance ★★ ⚠ same residue
RECQL p.Ser394Thr Uncertain significance ★ ⚠ same residue
RECQL p.Ser394= Likely benign ★ 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

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-ser394phe (accessed [today's date]).

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