Is USP18 p.Arg258Ter (c.772C>T) pathogenic?

USP18 p.Arg258Ter (c.772C>T) is classified Pathogenic in USP18 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-21). Very rare (popmax 0.00332%, sas); Associated with pseudo-TORCH syndrome 2.

What condition is associated with USP18 p.Arg258Ter (c.772C>T)?

USP18 p.Arg258Ter (c.772C>T) is associated with pseudo-TORCH syndrome 2 (ClinVar).

How common is USP18 p.Arg258Ter (c.772C>T) in the general population?

USP18 p.Arg258Ter (c.772C>T) is very rare (popmax 0.00332%, sas) (gnomAD).

How is Pseudo-TORCH syndrome type 2 inherited?

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

USP18 p.Arg258Ter

c.772C>T · VCV3256725

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00332%, sas)

Conditions

pseudo-TORCH syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 8 of 11
Splicing
SpliceAI	Δ0.27	acceptor gain · deltas
Pangolin	Δ0.24	gain · loss 0.10 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.73	phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00332% South Asian · 3/90,226 alleles

Filtering AF 0.00232% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00203%

Overall 0.00262% 42/1,601,870 alleles · very rare exomes 41/1,459,290 · genomes 1/142,580 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00332%	30,075
Remaining individualsnot grpmax-eligible	0.00321%	31,106
European (non-Finnish)	0.00314%	31,800

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: USP18
Protein: p.Arg258Ter
Coding: c.772C>T
MANE Select: NM_017414
Type: single nucleotide variant
Location: chr22:18170801 (GRCh38)
Gene constraint: LOEUF 0.459 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.60 · 2 PDB
Residue 258: the usp domain; a UniProt-annotated variant site (in ptorch2)

Full USP18 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pseudo-TORCH syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Pseudo-TORCH syndrome type 2 (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Neonatal

Similar variants

USP18 c.891+1G>T Likely pathogenic ★ same condition
USP18 p.Gln218Ter Likely pathogenic ★ same condition
USP18 p.Glu303Lys Conflicting classifications of pathogenicity ★ ⚠ same condition
USP18 p.Pro120Ser Uncertain significance ★ ⚠ same condition
USP18 c.1073+1G>A Pathogenic/Likely pathogenic same condition
USP18 p.Ser2Asn Uncertain significance ★★ ⚠ same type
USP18 p.Thr80Ile Uncertain significance ★★ ⚠ same type
USP18 c.158-5T>G Benign/Likely benign ★★ 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/usp18-p-arg258ter (accessed [today's date]).

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