Is USP30 p.Pro90Ser (c.268C>T) pathogenic?

USP30 p.Pro90Ser (c.268C>T) is classified Uncertain significance in USP30 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-14). AlphaMissense: ambiguous (0.4139); Ultra-rare (popmax 0.025%, amr).

How common is USP30 p.Pro90Ser (c.268C>T) in the general population?

USP30 p.Pro90Ser (c.268C>T) is ultra-rare (popmax 0.025%, amr) (gnomAD).

What do computational predictors say about USP30 p.Pro90Ser (c.268C>T)?

AlphaMissense predicts ambiguous (score 0.4139) — an in-silico prediction, not a clinical call.

USP30 p.Pro90Ser

c.268C>T · VCV3814175

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4139 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4139	ambiguous
REVEL	0.288	benign-leaning
SaProt	LLR -6.67	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 4.9, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 33 kb · p 5.8e-07 · regional, not allelic
Overall
CADD	27.9	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 0.025% Admixed American · 15/59,996 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.00112% 18/1,614,050 alleles · ultra-rare exomes 15/1,461,886 · genomes 3/152,164 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.025%	4,000
European (non-Finnish)	0.000254%	393,346

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: USP30
Protein: p.Pro90Ser
Coding: c.268C>T
MANE Select: NM_032663
Type: single nucleotide variant
Location: chr12:109058000 (GRCh38)
Gene constraint: LOEUF 0.757 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.29 · 8 PDB
Residue 90: an α-helix; the usp domain

Full USP30 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP30 p.Ala12Val Uncertain significance ★ ⚠ same type
USP30 p.Ala25Glu Uncertain significance ★ ⚠ same type
USP30 p.Ala25Thr Uncertain significance ★ ⚠ same type
USP30 p.Ala396Asp Uncertain significance ★ ⚠ same type
USP30 p.Ala417Val Uncertain significance ★ ⚠ same type
USP30 p.Ala494Thr Uncertain significance ★ ⚠ same type
USP30 p.Ala6Thr Uncertain significance ★ ⚠ same type
USP30 p.Arg105Gly 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/usp30-p-pro90ser (accessed [today's date]).

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