Is USP20 p.Pro705His (c.2114C>A) pathogenic?

USP20 p.Pro705His (c.2114C>A) is classified Uncertain significance in USP20 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely benign (0.1572); Ultra-rare (popmax 0.0493%, mid).

How common is USP20 p.Pro705His (c.2114C>A) in the general population?

USP20 p.Pro705His (c.2114C>A) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about USP20 p.Pro705His (c.2114C>A)?

AlphaMissense predicts likely benign (score 0.1572) — an in-silico prediction, not a clinical call.

USP20 p.Pro705His

c.2114C>A · VCV4197141

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1572 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1572	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -7.35	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 28 kb · p 1.1e-08 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0493% Middle Eastern · 3/6,082 alleles

Filtering AF 0.0451% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0437%

Overall 0.0377% 608/1,613,160 alleles · ultra-rare exomes 557/1,460,940 · genomes 51/152,220 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,027
European (non-Finnish)	0.0484%	2,066
Remaining individualsnot grpmax-eligible	0.0288%	3,470
Admixed American	0.0167%	5,996
African / African-American	0.004%	24,979
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,584
Finnishnot grpmax-eligible	0.00316%	31,695

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.Pro705His
Coding: c.2114C>A
MANE Select: NM_001110303
Type: single nucleotide variant
Location: chr9:129875375 (GRCh38)
Gene constraint: LOEUF 0.784 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.11 · 1 PDB
Residue 705: the dusp 1 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-pro705his (accessed [today's date]).

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