Is USP8 p.Phe619= (c.1857T>C) pathogenic?

USP8 p.Phe619= (c.1857T>C) is classified Benign in USP8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-27). Common (popmax 25.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with hereditary spastic paraplegia.

What condition is associated with USP8 p.Phe619= (c.1857T>C)?

USP8 p.Phe619= (c.1857T>C) is associated with hereditary spastic paraplegia (ClinVar).

USP8 p.Phe619=

Q: How common is USP8 p.Phe619= (c.1857T>C) in the general population?

USP8 p.Phe619= (c.1857T>C) is common (popmax 25.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1857T>C · rs10220843 · VCV458314

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 25.1%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

hereditary spastic paraplegia

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 0.003	GERP -0.069, phastCons 0.99
Overall
CADD	8.313	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 25.1% African / African-American · 18,715/74,680 alleles

Filtering AF 24.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 24.6%

Overall 3.87% 62,389/1,611,854 alleles · common exomes 48,714/1,459,680 · genomes 13,675/152,174 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	25.1%	4
Remaining individualsnot grpmax-eligible	4.52%	22
Middle Eastern	4.12%	24
Admixed American	3.95%	25
Ashkenazi Jewishnot grpmax-eligible	3.49%	29
South Asian	3.05%	33
European (non-Finnish)	2.81%	36
East Asian	1.47%	68
Finnishnot grpmax-eligible	1.07%	94
Amishnot grpmax-eligible	0.219%	456

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: USP8
Protein: p.Phe619=
Coding: c.1857T>C
MANE Select: NM_005154
dbSNP: rs10220843
Type: single nucleotide variant
Location: chr15:50484328 (GRCh38)
Gene constraint: LOEUF 0.28 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.98 · 9 PDB
Residue 619: the 'disordered' region

Full USP8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

USP8 p.Arg133Trp Uncertain significance ★★ ⚠ same condition
USP8 p.Phe875Ser Uncertain significance ★★ ⚠ same condition
USP8 p.Pro703His Uncertain significance ★★ ⚠ same condition
USP8 c.104+16C>T Benign ★★ same condition
USP8 c.250-8A>C Benign ★★ same condition
USP8 p.Ala348Thr Benign ★★ same condition
USP8 p.Arg483Gln Benign ★★ same condition
USP8 p.Arg763Trp Benign ★★ ⚠ 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/usp8-p-phe619 (accessed [today's date]).

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