Is STS p.Ser336Leu (c.1007C>T) pathogenic?

STS p.Ser336Leu (c.1007C>T) is classified Conflicting classifications of pathogenicity in STS (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-08-13). AlphaMissense: likely pathogenic (0.8841); Absent from gnomAD v4.1; Associated with recessive X-linked ichthyosis.

What condition is associated with STS p.Ser336Leu (c.1007C>T)?

STS p.Ser336Leu (c.1007C>T) is associated with recessive X-linked ichthyosis (ClinVar).

How common is STS p.Ser336Leu (c.1007C>T) in the general population?

STS p.Ser336Leu (c.1007C>T) is absent from gnomAD v4.1 (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.Ser336Leu (c.1007C>T)?

AlphaMissense predicts likely pathogenic (score 0.8841) — an in-silico prediction, not a clinical call.

STS p.Ser336Leu

c.1007C>T · rs137853167 · VCV10554

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8841 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

recessive X-linked ichthyosis

Computational evidence

Protein change
AlphaMissense	0.8841	likely pathogenic
REVEL	0.758	pathogenic-leaning
SaProt	LLR -18.36	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.4	GERP 5.7, phastCons 0.99
Regional constraint	o/e 0.79	unconstrained · MANE · 72 kb · p 0.00048 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S341L vs ClinVar S336L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: STS
Protein: p.Ser336Leu
Coding: c.1007C>T
MANE Select: NM_001320752
dbSNP: rs137853167
Type: single nucleotide variant
Location: chrX:7305109 (GRCh38)
Structure: AlphaFold pLDDT 94.31 · 2 PDB
Residue 336: a β-strand

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.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
STS c.1082-18T>C Uncertain significance ★ 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-ser336leu (accessed [today's date]).

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