Is USP13 p.Val412Met (c.1234G>A) pathogenic?

USP13 p.Val412Met (c.1234G>A) is classified Uncertain significance in USP13 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-19). AlphaMissense: ambiguous (0.4867); Ultra-rare (popmax 0.0107%, nfe).

How common is USP13 p.Val412Met (c.1234G>A) in the general population?

USP13 p.Val412Met (c.1234G>A) is ultra-rare (popmax 0.0107%, nfe) (gnomAD).

What do computational predictors say about USP13 p.Val412Met (c.1234G>A)?

AlphaMissense predicts ambiguous (score 0.4867) — an in-silico prediction, not a clinical call.

USP13 p.Val412Met

c.1234G>A · rs199512457 · VCV2270632

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4867 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4867	ambiguous
REVEL	0.261	benign-leaning
SaProt	LLR -5.93	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 131 kb · p 7.3e-06 · regional, not allelic
Overall
CADD	25.0	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 0.0107% European (non-Finnish) · 126/1,179,952 alleles

Filtering AF 0.00911% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00855%

Overall 0.00929% 150/1,613,974 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0224%	4,463
European (non-Finnish)grpmax	0.0107%	9,365
African / African-American	0.00934%	10,706
South Asian	0.0022%	45,534
Admixed American	0.00167%	59,998

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: USP13
Protein: p.Val412Met
Coding: c.1234G>A
MANE Select: NM_003940
dbSNP: rs199512457
Type: single nucleotide variant
Location: chr3:179730689 (GRCh38)
Gene constraint: LOEUF 0.767 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.80 · 2 PDB
Residue 412: the usp domain

Full USP13 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

USP13 p.Val412Leu Uncertain significance ★ ⚠ same residue
USP13 c.1921+5C>T Benign/Likely benign ★★ same type
USP13 p.Cys214= Benign ★★ same type
USP13 p.Thr492= Benign ★★ same type
USP13 p.Ala103Val Uncertain significance ★ ⚠ same type
USP13 p.Ala21Thr Uncertain significance ★ ⚠ same type
USP13 p.Ala504Val Uncertain significance ★ ⚠ same type
USP13 p.Ala516Val 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/usp13-p-val412met (accessed [today's date]).

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