Is USP14 p.Asp76Val (c.227A>T) pathogenic?

USP14 p.Asp76Val (c.227A>T) is classified Uncertain significance in USP14 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely pathogenic (0.6596); Very rare (popmax 0.00167%, amr).

How common is USP14 p.Asp76Val (c.227A>T) in the general population?

USP14 p.Asp76Val (c.227A>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about USP14 p.Asp76Val (c.227A>T)?

AlphaMissense predicts likely pathogenic (score 0.6596) — an in-silico prediction, not a clinical call.

USP14 p.Asp76Val

c.227A>T · rs1452455542 · VCV2303382

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6596 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6596	likely pathogenic
REVEL	0.261	benign-leaning
SaProt	LLR -9.08	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.3	GERP 2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 53 kb · p 8.1e-07 · regional, not allelic
Overall
CADD	24.8	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 0.00167% Admixed American · 1/59,844 alleles

Overall 6.2e-05% 1/1,613,324 alleles · very rare exomes 1/1,461,038 · genomes 0/152,286 · 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: USP14
Protein: p.Asp76Val
Coding: c.227A>T
MANE Select: NM_005151
dbSNP: rs1452455542
Type: single nucleotide variant
Location: chr18:178964 (GRCh38)
Gene constraint: LOEUF 0.627 · pLI 0.08 (gnomAD)
Structure: AlphaFold pLDDT 82.45 · 23 PDB
Residue 76: the ubiquitin-like domain; a β-strand

Full USP14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP14 p.Asp76His Uncertain significance ★ ⚠ same residue
USP14 c.943-17A>C Benign ★★ same type
USP14 p.Ala35= Benign ★★ same type
USP14 p.Leu358= Benign ★★ same type
USP14 c.1036-1G>A Uncertain significance ★ same type
USP14 c.1225+4A>G Uncertain significance ★ same type
USP14 c.761+6C>T Uncertain significance ★ same type
USP14 p.Ala155Gly 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/usp14-p-asp76val (accessed [today's date]).

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