Is USE1 p.Ser130Cys (c.389C>G) pathogenic?

USE1 p.Ser130Cys (c.389C>G) is classified Uncertain significance in USE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). AlphaMissense: likely benign (0.0843); Very rare (popmax 0.000339%, nfe).

How common is USE1 p.Ser130Cys (c.389C>G) in the general population?

USE1 p.Ser130Cys (c.389C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about USE1 p.Ser130Cys (c.389C>G)?

AlphaMissense predicts likely benign (score 0.0843) — an in-silico prediction, not a clinical call.

USE1 p.Ser130Cys

c.389C>G · rs1006849955 · VCV2354447

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0843 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0843	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -9.96	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 0.53	GERP -0.11, phastCons 0.18
Overall
CADD	19.71	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 0.000339% European (non-Finnish) · 4/1,178,644 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,611,440 alleles · very rare exomes 3/1,459,344 · genomes 1/152,096 · 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: USE1
Protein: p.Ser130Cys
Coding: c.389C>G
MANE Select: NM_018467
dbSNP: rs1006849955
Type: single nucleotide variant
Location: chr19:17217457 (GRCh38)
Structure: AlphaFold pLDDT 82.49 · 5 PDB
Residue 130: the ubc core domain; a β-strand

Full USE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

UBE2Z p.Arg245Gln Uncertain significance ★ same type
UBE2Z p.Arg289His Uncertain significance ★ same type
UBE2Z p.Asn180Asp Uncertain significance ★ ⚠ same type
UBE2Z p.Gln298Lys Uncertain significance ★ ⚠ same type
UBE2Z p.Glu265Lys Uncertain significance ★ ⚠ same type
UBE2Z p.His132Asp Uncertain significance ★ ⚠ same type
UBE2Z p.His329Arg Uncertain significance ★ ⚠ same type
UBE2Z p.Val121Ile 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/use1-p-ser130cys (accessed [today's date]).

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