Is USP25 p.Ala705Val (c.2114C>T) pathogenic?

USP25 p.Ala705Val (c.2114C>T) is classified Uncertain significance in USP25 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-20). AlphaMissense: likely benign (0.0921); Very rare (popmax 0.00446%, eas).

How common is USP25 p.Ala705Val (c.2114C>T) in the general population?

USP25 p.Ala705Val (c.2114C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about USP25 p.Ala705Val (c.2114C>T)?

AlphaMissense predicts likely benign (score 0.0921) — an in-silico prediction, not a clinical call.

USP25 p.Ala705Val

c.2114C>T · rs775871814 · VCV3187309

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0921 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0921	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -7.86	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 1.7	phastCons 0.46
Regional constraint	o/e 1.00	unconstrained · MANE · 47 kb · p 0.91 · regional, not allelic
Overall
CADD	20.6	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 0.00446% East Asian · 2/44,858 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000186% 3/1,613,914 alleles · very rare exomes 1/1,461,792 · genomes 2/152,122 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,429
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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: USP25
Protein: p.Ala705Val
Coding: c.2114C>T
MANE Select: NM_001283041
dbSNP: rs775871814
Type: single nucleotide variant
Location: chr21:15833468 (GRCh38)
Gene constraint: LOEUF 0.635 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.12 · 7 PDB

Full USP25 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP25 p.Arg217Gln Uncertain significance ★★ ⚠ same type
USP25 p.Val596Ile Uncertain significance ★★ ⚠ same type
USP25 p.Ala474Thr Uncertain significance ★ ⚠ same type
USP25 p.Ala659Ser Uncertain significance ★ ⚠ same type
USP25 p.Ala718Val Uncertain significance ★ ⚠ same type
USP25 p.Ala919Thr Uncertain significance ★ ⚠ same type
USP25 p.Arg1058Gln Uncertain significance ★ ⚠ same type
USP25 p.Arg1112Gln 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/usp25-p-ala705val (accessed [today's date]).

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