Is USP53 p.Ile706Phe (c.2116A>T) pathogenic?

USP53 p.Ile706Phe (c.2116A>T) is classified Uncertain significance in USP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-21). AlphaMissense: likely benign (0.0934); Very rare (popmax 0.00801%, afr); Associated with Inborn genetic diseases.

What condition is associated with USP53 p.Ile706Phe (c.2116A>T)?

USP53 p.Ile706Phe (c.2116A>T) is associated with Inborn genetic diseases (ClinVar).

How common is USP53 p.Ile706Phe (c.2116A>T) in the general population?

USP53 p.Ile706Phe (c.2116A>T) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about USP53 p.Ile706Phe (c.2116A>T)?

AlphaMissense predicts likely benign (score 0.0934) — an in-silico prediction, not a clinical call.

USP53 p.Ile706Phe

c.2116A>T · VCV3814425

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0934 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0934	likely benign
REVEL	0.107	moderately benign-leaning
SaProt	LLR -6.28	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 -0.53	GERP -3.6
Regional constraint	o/e 0.92	unconstrained · MANE · 53 kb · p 0.0026 · regional, not allelic
Overall
CADD	14.48	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 0.00801% African / African-American · 6/74,908 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000558% 9/1,613,286 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,485
South Asian	0.0033%	30,267

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.Ile706Phe
Coding: c.2116A>T
MANE Select: NM_001371395
Type: single nucleotide variant
Location: chr4:119271976 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.34
Residue 706: 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.Ile706= Likely benign ★ same residue
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

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-ile706phe (accessed [today's date]).

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