Is STS p.Arg269Gln (c.806G>A) pathogenic?

STS p.Arg269Gln (c.806G>A) is classified Uncertain significance in STS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-04). AlphaMissense: likely benign (0.0794); Ultra-rare (popmax 0.023%, mid); Associated with recessive X-linked ichthyosis.

What condition is associated with STS p.Arg269Gln (c.806G>A)?

STS p.Arg269Gln (c.806G>A) is associated with recessive X-linked ichthyosis (ClinVar).

How common is STS p.Arg269Gln (c.806G>A) in the general population?

STS p.Arg269Gln (c.806G>A) is ultra-rare (popmax 0.023%, mid) (gnomAD).

How is Recessive X-linked ichthyosis inherited?

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

What do computational predictors say about STS p.Arg269Gln (c.806G>A)?

AlphaMissense predicts likely benign (score 0.0794) — an in-silico prediction, not a clinical call.

STS p.Arg269Gln

c.806G>A · rs1382685156 · VCV3067945

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0794 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.023%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

recessive X-linked ichthyosis

Computational evidence

Protein change
AlphaMissense	0.0794	likely benign
REVEL	0.537	indeterminate
SaProt	LLR -5.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.46	donor loss · deltas
Pangolin	Δ0.30	loss · gain 0.20 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.4	GERP 5.7, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 72 kb · p 0.00048 · regional, not allelic
Overall
CADD	25.4	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R274Q vs ClinVar R269Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.023% Middle Eastern · 1/4,345 alleles

Filtering AF 0.00126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00174% 21/1,207,740 alleles · ultra-rare exomes 20/1,095,904 · genomes 1/111,836 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.023%	4,345
Remaining individualsnot grpmax-eligible	0.0021%	47,583
European (non-Finnish)	0.00201%	49,714
South Asian	0.00176%	56,753

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: STS
Protein: p.Arg269Gln
Coding: c.806G>A
MANE Select: NM_001320752
dbSNP: rs1382685156
Type: single nucleotide variant
Location: chrX:7259772 (GRCh38)
Structure: AlphaFold pLDDT 94.31 · 2 PDB

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

Disease context

recessive X-linked ichthyosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Recessive X-linked ichthyosis (Orphanet):

Inheritance: X-linked recessive
Onset: Neonatal
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

STS p.Arg269Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
STS p.Gly354Arg Likely pathogenic ★★ same condition
STS c.383-16C>T Benign/Likely benign ★★ same condition
STS c.1241+1G>C Likely pathogenic ★ same condition
STS c.806+1G>A Pathogenic ★ same condition
STS p.Gly128Arg Likely pathogenic ★ same condition
STS p.Gly370Cys Likely pathogenic ★ same condition
STS p.Trp91Ter 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/sts-p-arg269gln (accessed [today's date]).

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