Is USP45 p.Pro248Ser (c.742C>T) pathogenic?

USP45 p.Pro248Ser (c.742C>T) is classified Uncertain significance in USP45 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-24). AlphaMissense: ambiguous (0.3468); Very rare (popmax 0.00409%, afr).

How common is USP45 p.Pro248Ser (c.742C>T) in the general population?

USP45 p.Pro248Ser (c.742C>T) is very rare (popmax 0.00409%, afr) (gnomAD).

What do computational predictors say about USP45 p.Pro248Ser (c.742C>T)?

AlphaMissense predicts ambiguous (score 0.3468) — an in-silico prediction, not a clinical call.

USP45 p.Pro248Ser

c.742C>T · VCV3814381

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3468 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00409%, afr)

Computational evidence

Protein change
AlphaMissense	0.3468	ambiguous
REVEL	0.315	indeterminate
SaProt	LLR -8.17	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 75 kb · p 0.15 · regional, not allelic
Overall
CADD	27.4	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 0.00409% African / African-American · 3/73,368 alleles

Filtering AF 0.00109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000501%

Overall 0.000191% 3/1,567,778 alleles · very rare exomes 2/1,415,704 · genomes 1/152,074 · joint denominator

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: USP45
Protein: p.Pro248Ser
Coding: c.742C>T
MANE Select: NM_001346022
Type: single nucleotide variant
Location: chr6:99482856 (GRCh38)
Gene constraint: LOEUF 1.09 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.28
Residue 248: the usp domain

Full USP45 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP45 p.Gly570Glu Uncertain significance ★★ ⚠ same type
USP45 c.845+2T>C Benign ★★ same type
USP45 p.Ile418Thr Benign/Likely benign ★★ same type
USP45 p.Arg443Ter Likely pathogenic ★ same type
USP45 p.Ser508Ter Pathogenic ★ same type
USP45 c.2073+1G>T Uncertain significance ★ same type
USP45 c.377+5G>A Uncertain significance ★ same type
USP45 c.-10-2A>G 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/usp45-p-pro248ser (accessed [today's date]).

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