Is USP18 p.His247Arg (c.740A>G) pathogenic?

USP18 p.His247Arg (c.740A>G) is classified Uncertain significance in USP18 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-23). AlphaMissense: likely benign (0.078); Very rare (popmax 0.000509%, nfe); Associated with Inborn genetic diseases.

What condition is associated with USP18 p.His247Arg (c.740A>G)?

USP18 p.His247Arg (c.740A>G) is associated with Inborn genetic diseases (ClinVar).

How common is USP18 p.His247Arg (c.740A>G) in the general population?

USP18 p.His247Arg (c.740A>G) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about USP18 p.His247Arg (c.740A>G)?

AlphaMissense predicts likely benign (score 0.078) — an in-silico prediction, not a clinical call.

USP18 p.His247Arg

c.740A>G · VCV3331354

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.078 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.078	likely benign
REVEL	0.034	moderately benign-leaning
SaProt	LLR -5.39	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 0.26
Regional constraint	o/e 0.36	constrained · MANE · 2,864 bp · p 4.3e-10 · regional, not allelic
Overall
CADD	11.6	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 0.000509% European (non-Finnish) · 6/1,178,646 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000411% 6/1,461,396 alleles · very rare

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.His247Arg
Coding: c.740A>G
MANE Select: NM_017414
Type: single nucleotide variant
Location: chr22:18170769 (GRCh38)
Gene constraint: LOEUF 0.459 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.60 · 2 PDB
Residue 247: 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

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-his247arg (accessed [today's date]).

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