Is USP53 p.Ser962Arg (c.2886T>G) pathogenic?

USP53 p.Ser962Arg (c.2886T>G) is classified Benign in USP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1672); Common (popmax 36.7%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about USP53 p.Ser962Arg (c.2886T>G)?

AlphaMissense predicts likely benign (score 0.1672) — an in-silico prediction, not a clinical call.

USP53 p.Ser962Arg

Q: How common is USP53 p.Ser962Arg (c.2886T>G) in the general population?

USP53 p.Ser962Arg (c.2886T>G) is common (popmax 36.7%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2886T>G · rs3749591 · VCV2135314

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1672 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 36.7%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1672	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -7.68	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 -2.2	GERP -3.5
Regional constraint	o/e 0.92	unconstrained · MANE · 53 kb · p 0.0026 · regional, not allelic
Overall
CADD	10.39	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 36.7% East Asian · 16,479/44,866 alleles

Filtering AF 36.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 36.1%

Overall 30.3% 488,865/1,613,810 alleles · common exomes 449,597/1,461,786 · genomes 39,268/152,024 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	36.7%	3
European (non-Finnish)	32.7%	3
Admixed American	28.9%	3
Amishnot grpmax-eligible	28.8%	3
Remaining individualsnot grpmax-eligible	28.7%	3
Finnishnot grpmax-eligible	26.7%	4
Ashkenazi Jewishnot grpmax-eligible	21.8%	5
Middle Eastern	20.3%	5
South Asian	17.7%	6
African / African-American	13.8%	7

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.Ser962Arg
Coding: c.2886T>G
MANE Select: NM_001371395
dbSNP: rs3749591
Type: single nucleotide variant
Location: chr4:119292875 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.34
Residue 962: a UniProt-annotated variant site (in pfic7); a UniProt-annotated variant site (in)

Full USP53 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP53 p.Arg111Ter Likely pathogenic ★★ same type
USP53 p.Arg338Ter Pathogenic ★★ same type
USP53 p.Arg476Ter Pathogenic/Likely pathogenic ★★ same type
USP53 p.Arg520Ter Pathogenic ★★ same type
USP53 p.Arg582Ter Pathogenic/Likely pathogenic ★★ same type
USP53 p.Arg58Gln Uncertain significance ★★ ⚠ same type
USP53 p.Asn97Asp Uncertain significance ★★ ⚠ same type
USP53 p.Asn97Ser Uncertain significance ★★ ⚠ same type

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-ser962arg (accessed [today's date]).

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