Is USP53 p.Leu93Phe (c.277C>T) pathogenic?

USP53 p.Leu93Phe (c.277C>T) is classified Uncertain significance in USP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-13). AlphaMissense: likely pathogenic (0.8191); Ultra-rare (popmax 0.0411%, nfe); Associated with Inborn genetic diseases.

What condition is associated with USP53 p.Leu93Phe (c.277C>T)?

USP53 p.Leu93Phe (c.277C>T) is associated with Inborn genetic diseases (ClinVar).

How common is USP53 p.Leu93Phe (c.277C>T) in the general population?

USP53 p.Leu93Phe (c.277C>T) is ultra-rare (popmax 0.0411%, nfe) (gnomAD).

What do computational predictors say about USP53 p.Leu93Phe (c.277C>T)?

AlphaMissense predicts likely pathogenic (score 0.8191) — an in-silico prediction, not a clinical call.

USP53 p.Leu93Phe

c.277C>T · rs199956888 · VCV2305117

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8191 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0411%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8191	likely pathogenic
REVEL	0.386	indeterminate
SaProt	LLR -9.17	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 53 kb · p 0.0026 · regional, not allelic
Overall
CADD	27.7	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 0.0411% European (non-Finnish) · 485/1,180,034 alleles

Filtering AF 0.0381% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0368%

Overall 0.0322% 520/1,613,946 alleles · ultra-rare exomes 494/1,461,744 · genomes 26/152,202 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0416%	2,403
European (non-Finnish)grpmax	0.0411%	2,433
African / African-American	0.00667%	14,985
Admixed American	0.00667%	14,999

Remaining individuals 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: USP53
Protein: p.Leu93Phe
Coding: c.277C>T
MANE Select: NM_001371395
dbSNP: rs199956888
Type: single nucleotide variant
Location: chr4:119248787 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.34
Residue 93: the usp domain; a UniProt-annotated variant site (in pfic7)

Full USP53 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

USP53 p.Asn97Asp Uncertain significance ★★ ⚠ same condition
USP53 p.Asn97Ser Uncertain significance ★★ ⚠ same condition
USP53 p.Asp482His Uncertain significance ★★ ⚠ same condition
USP53 p.Ile613Thr Uncertain significance ★★ ⚠ same condition
USP53 p.Ser185Phe Uncertain significance ★★ ⚠ same condition
USP53 p.Ser334Phe Uncertain significance ★★ ⚠ same condition
USP53 p.Thr1046Met Uncertain significance ★★ ⚠ same condition
USP53 p.Val845Ile 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/usp53-p-leu93phe (accessed [today's date]).

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