Is USP18 p.Arg44Cys (c.130C>T) pathogenic?

USP18 p.Arg44Cys (c.130C>T) is classified Uncertain significance in USP18 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely benign (0.0825); Ultra-rare (popmax 0.0154%, sas); Associated with Inborn genetic diseases.

What condition is associated with USP18 p.Arg44Cys (c.130C>T)?

USP18 p.Arg44Cys (c.130C>T) is associated with Inborn genetic diseases (ClinVar).

How common is USP18 p.Arg44Cys (c.130C>T) in the general population?

USP18 p.Arg44Cys (c.130C>T) is ultra-rare (popmax 0.0154%, sas) (gnomAD).

What do computational predictors say about USP18 p.Arg44Cys (c.130C>T)?

AlphaMissense predicts likely benign (score 0.0825) — an in-silico prediction, not a clinical call.

USP18 p.Arg44Cys

c.130C>T · VCV4197092

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0825 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0825	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -8.31	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.013
Regional constraint	o/e 0.83	unconstrained · MANE · 10 kb · p 0.0088 · regional, not allelic
Overall
CADD	7.321	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0154% South Asian · 14/91,082 alleles

Filtering AF 0.00919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00124% 20/1,613,980 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0154%	6,506
European (non-Finnish)	0.000508%	196,667

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.Arg44Cys
Coding: c.130C>T
MANE Select: NM_017414
Type: single nucleotide variant
Location: chr22:18157793 (GRCh38)
Gene constraint: LOEUF 0.459 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.60 · 2 PDB
Residue 44: the 'disordered' region; the 'mediates interaction with ifnar2' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

USP18 p.Ser2Asn Uncertain significance ★★ ⚠ same condition
USP18 p.Thr80Ile Uncertain significance ★★ ⚠ same condition
USP18 p.Arg289Gln Likely benign ★★ same condition
USP18 p.Ala212Ser Uncertain significance ★ ⚠ same condition
USP18 p.Arg114Gln Uncertain significance ★ ⚠ same condition
USP18 p.Arg119Trp Uncertain significance ★ ⚠ same condition
USP18 p.Arg171Trp Uncertain significance ★ ⚠ same condition
USP18 p.Arg238Leu 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/usp18-p-arg44cys (accessed [today's date]).

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