Is USB1 p.Arg219Cys (c.655C>T) pathogenic?

USB1 p.Arg219Cys (c.655C>T) is classified Conflicting classifications of pathogenicity in USB1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-11). AlphaMissense: likely benign (0.0851); Rare (popmax 0.118%, eas); Associated with Inborn genetic diseases.

What condition is associated with USB1 p.Arg219Cys (c.655C>T)?

USB1 p.Arg219Cys (c.655C>T) is associated with Inborn genetic diseases (ClinVar).

How common is USB1 p.Arg219Cys (c.655C>T) in the general population?

USB1 p.Arg219Cys (c.655C>T) is rare (popmax 0.118%, eas) (gnomAD).

What do computational predictors say about USB1 p.Arg219Cys (c.655C>T)?

AlphaMissense predicts likely benign (score 0.0851) — an in-silico prediction, not a clinical call.

USB1 p.Arg219Cys

c.655C>T · rs554516072 · VCV1129490

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0851 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.118%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0851	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -8.69	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 -0.017	GERP -2.5
Regional constraint	o/e 0.95	unconstrained · MANE · 19 kb · p 0.36 · regional, not allelic
Overall
CADD	17.63	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.118% East Asian · 53/44,874 alleles

Filtering AF 0.0927% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0836%

Overall 0.00471% 76/1,614,172 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.118%	847
Remaining individualsnot grpmax-eligible	0.0128%	7,814
South Asian	0.0022%	45,538
Admixed American	0.00167%	60,020
African / African-American	0.00133%	75,048
European (non-Finnish)	0.000932%	107,275

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: USB1
Protein: p.Arg219Cys
Coding: c.655C>T
MANE Select: NM_024598
dbSNP: rs554516072
Type: single nucleotide variant
Location: chr16:58019017 (GRCh38)
Gene constraint: LOEUF 1.016 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 83.91 · 5 PDB
Residue 219: an α-helix

Full USB1 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

USB1 p.Arg219Ser Uncertain significance ★ ⚠ same residue
USB1 p.Arg219His Uncertain significance ★ ⚠ same residue
USB1 p.Ala106Ser Uncertain significance ★★ ⚠ same condition
USB1 p.Ala218Thr Uncertain significance ★★ ⚠ same condition
USB1 p.Ala218Val Uncertain significance ★★ ⚠ same condition
USB1 p.Arg112Gln Uncertain significance ★★ ⚠ same condition
USB1 p.Arg112Trp Uncertain significance ★★ ⚠ same condition
USB1 p.Arg130Cys 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/usb1-p-arg219cys (accessed [today's date]).

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