Is USP53 p.Pro617Ser (c.1849C>T) pathogenic?

USP53 p.Pro617Ser (c.1849C>T) is classified Likely benign in USP53 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-13). AlphaMissense: likely benign (0.076); Low-frequency (popmax 1.27%, mid).

How common is USP53 p.Pro617Ser (c.1849C>T) in the general population?

USP53 p.Pro617Ser (c.1849C>T) is low-frequency (popmax 1.27%, mid) (gnomAD).

What do computational predictors say about USP53 p.Pro617Ser (c.1849C>T)?

AlphaMissense predicts likely benign (score 0.076) — an in-silico prediction, not a clinical call.

USP53 p.Pro617Ser

c.1849C>T · rs147140509 · VCV708168

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.076 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.27%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.076	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -5.05	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 0.38	GERP -0.76, phastCons 0.001
Regional constraint	o/e 0.92	unconstrained · MANE · 53 kb · p 0.0026 · regional, not allelic
Overall
CADD	0.359	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 1.27% Middle Eastern · 77/6,058 alleles

Filtering AF 1.04% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.958%

Overall 0.435% 7,015/1,613,914 alleles · low-frequency exomes 6,574/1,461,724 · genomes 441/152,190 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.27%	79
Ashkenazi Jewishnot grpmax-eligible	0.561%	178
Remaining individualsnot grpmax-eligible	0.493%	203
European (non-Finnish)	0.491%	204
South Asian	0.343%	292
Admixed American	0.338%	296
Finnishnot grpmax-eligible	0.136%	735
African / African-American	0.0947%	1,056

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.Pro617Ser
Coding: c.1849C>T
MANE Select: NM_001371395
dbSNP: rs147140509
Type: single nucleotide variant
Location: chr4:119271709 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.34
Residue 617: a UniProt-annotated variant site (in pfic7); the 'disordered' region

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

Similar variants

USP53 p.Pro617Arg Uncertain significance ★ ⚠ same residue
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

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-pro617ser (accessed [today's date]).

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