Is USP18 p.Phe73= (c.219C>T) pathogenic?

USP18 p.Phe73= (c.219C>T) is classified Benign/Likely benign in USP18 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-04-07). Rare (popmax 0.107%, nfe).

How common is USP18 p.Phe73= (c.219C>T) in the general population?

USP18 p.Phe73= (c.219C>T) is rare (popmax 0.107%, nfe) (gnomAD).

USP18 p.Phe73=

c.219C>T · rs138144879 · VCV723623

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.107%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.5
Overall
CADD	2.588	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.107% European (non-Finnish) · 1,258/1,179,990 alleles

Filtering AF 0.102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0997%

Overall 0.103% 1,664/1,614,126 alleles · rare exomes 1,532/1,461,820 · genomes 132/152,306 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.411%	243
European (non-Finnish)grpmax	0.107%	938
Remaining individualsnot grpmax-eligible	0.0736%	1,359
South Asian	0.0692%	1,446
Ashkenazi Jewishnot grpmax-eligible	0.0338%	2,960
Middle Eastern	0.0165%	6,062
African / African-American	0.016%	6,254
East Asian	0.0111%	8,976
Admixed American	0.01%	10,003

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe73=
Coding: c.219C>T
MANE Select: NM_017414
dbSNP: rs138144879
Type: single nucleotide variant
Location: chr22:18160233 (GRCh38)
Gene constraint: LOEUF 0.459 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.60 · 2 PDB
Residue 73: the usp domain; the 'mediates interaction with stat2' region

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

Similar variants

USP18 p.Ser2Asn Uncertain significance ★★ ⚠ same type
USP18 p.Thr80Ile Uncertain significance ★★ ⚠ same type
USP18 c.158-5T>G Benign/Likely benign ★★ same type
USP18 p.Arg289Gln Likely benign ★★ same type
USP18 p.Asn325Ser Benign/Likely benign ★★ same type
USP18 p.Asp211= Benign/Likely benign ★★ same type
USP18 p.Asp33Asn Likely benign ★★ same type
USP18 p.Ile323Val 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-phe73 (accessed [today's date]).

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