Is USP53 p.Arg235His (c.704G>A) pathogenic?

USP53 p.Arg235His (c.704G>A) is classified Uncertain significance in USP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-24). AlphaMissense: likely pathogenic (0.567); Very rare (popmax 0.00668%, amr); Associated with Inborn genetic diseases.

What condition is associated with USP53 p.Arg235His (c.704G>A)?

USP53 p.Arg235His (c.704G>A) is associated with Inborn genetic diseases (ClinVar).

How common is USP53 p.Arg235His (c.704G>A) in the general population?

USP53 p.Arg235His (c.704G>A) is very rare (popmax 0.00668%, amr) (gnomAD).

What do computational predictors say about USP53 p.Arg235His (c.704G>A)?

AlphaMissense predicts likely pathogenic (score 0.567) — an in-silico prediction, not a clinical call.

USP53 p.Arg235His

c.704G>A · VCV4634274

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.567 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.567	likely pathogenic
REVEL	0.421	indeterminate
SaProt	LLR -8.11	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.20	loss · gain 0.03 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 9.8	GERP 2.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 53 kb · p 0.0026 · regional, not allelic
Overall
CADD	32.0	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 0.00668% Admixed American · 4/59,892 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00105% 17/1,613,040 alleles · very rare exomes 15/1,461,052 · genomes 2/151,988 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00668%	14,973
African / African-American	0.00267%	37,431
Remaining individualsnot grpmax-eligible	0.0016%	62,438
South Asian	0.0011%	90,962
European (non-Finnish)	0.000763%	131,060

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.Arg235His
Coding: c.704G>A
MANE Select: NM_001371395
Type: single nucleotide variant
Location: chr4:119260535 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.34
Residue 235: 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.Arg235Leu Uncertain significance ★ ⚠ 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-arg235his (accessed [today's date]).

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