Is USP20 p.Ala830Val (c.2489C>T) pathogenic?

USP20 p.Ala830Val (c.2489C>T) is classified Uncertain significance in USP20 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: ambiguous (0.3455); Ultra-rare (popmax 0.0995%, mid).

How common is USP20 p.Ala830Val (c.2489C>T) in the general population?

USP20 p.Ala830Val (c.2489C>T) is ultra-rare (popmax 0.0995%, mid) (gnomAD).

What do computational predictors say about USP20 p.Ala830Val (c.2489C>T)?

AlphaMissense predicts ambiguous (score 0.3455) — an in-silico prediction, not a clinical call.

USP20 p.Ala830Val

c.2489C>T · rs377374790 · VCV2380687

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3455 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0995%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3455	ambiguous
REVEL	0.076	moderately benign-leaning
SaProt	LLR -10.43	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -0.23, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 28 kb · p 1.1e-08 · regional, not allelic
Overall
CADD	27.7	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 0.0995% Middle Eastern · 6/6,030 alleles

Filtering AF 0.0433% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0296%

Overall 0.00553% 89/1,609,144 alleles · ultra-rare exomes 83/1,457,000 · genomes 6/152,144 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0995%	1,005
Remaining individualsnot grpmax-eligible	0.0129%	7,782
South Asian	0.0122%	8,205
European (non-Finnish)	0.00518%	19,303
East Asian	0.00447%	22,369
African / African-American	0.00134%	74,864

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: USP20
Protein: p.Ala830Val
Coding: c.2489C>T
MANE Select: NM_001110303
dbSNP: rs377374790
Type: single nucleotide variant
Location: chr9:129878417 (GRCh38)
Gene constraint: LOEUF 0.784 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.11 · 1 PDB
Residue 830: the dusp 2 domain

Full USP20 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP20 p.Arg330Gly Uncertain significance ★★ ⚠ same type
USP20 p.Ile907= Benign ★★ same type
USP20 p.Pro367= Benign ★★ same type
USP20 p.Ser103Tyr Benign ★★ same type
USP20 p.Ser288= Benign ★★ same type
USP20 p.Ala260Ser Uncertain significance ★ ⚠ same type
USP20 p.Ala317Thr Uncertain significance ★ ⚠ same type
USP20 p.Ala355Thr 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/usp20-p-ala830val (accessed [today's date]).

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