Is STS p.Arg449His (c.1346G>A) pathogenic?

STS p.Arg449His (c.1346G>A) is classified Likely pathogenic in STS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-31). AlphaMissense: ambiguous (0.3951); Absent from gnomAD v4.1; Associated with STS-related disorder.

What condition is associated with STS p.Arg449His (c.1346G>A)?

STS p.Arg449His (c.1346G>A) is associated with STS-related disorder (ClinVar).

How common is STS p.Arg449His (c.1346G>A) in the general population?

STS p.Arg449His (c.1346G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about STS p.Arg449His (c.1346G>A)?

AlphaMissense predicts ambiguous (score 0.3951) — an in-silico prediction, not a clinical call.

STS p.Arg449His

c.1346G>A · rs2518726328 · VCV2634838

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3951 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,211,316)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

STS-related disorder

Computational evidence

Protein change
AlphaMissense	0.3951	ambiguous
REVEL	0.942	strongly pathogenic-leaning
SaProt	LLR -14.27	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	GERP 5.3, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 25 kb · p 0.038 · regional, not allelic
Overall
CADD	23.3	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 R454H vs ClinVar R449H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,211,316). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: STS
Protein: p.Arg449His
Coding: c.1346G>A
MANE Select: NM_001320752
dbSNP: rs2518726328
Type: single nucleotide variant
Location: chrX:7334090 (GRCh38)
Structure: AlphaFold pLDDT 94.31 · 2 PDB
Residue 449: a disulfide bond; a β-strand

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

Disease context

STS-related disorder

Similar variants

STS p.Gly354Ter Likely pathogenic ★ same condition
STS p.His131Tyr Likely pathogenic ★ same condition
STS p.Pro68Leu Conflicting classifications of pathogenicity ★ ⚠ same condition
STS p.Leu159fs Likely pathogenic ★ same condition
STS p.Leu53fs Likely pathogenic ★ same condition
STS p.Phe212fs Likely pathogenic ★ same condition
STS p.Gly354Arg Likely pathogenic ★★ same type
STS p.Arg381Ser 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/sts-p-arg449his (accessed [today's date]).

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