# NM_024598.4(USB1):c.213G>A (p.Val71=)

https://sugi.bio/variant/usb1-p-val71

## Summary

**USB1 p.Val71= (c.213G>A)** is classified **Conflicting classifications of pathogenicity** in USB1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-04-06). Ultra-rare (popmax 0.055%, amr).

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs369515724 · 4 submitters · ultra-rare (popmax 0.055%, amr)

## For patients & families {#patients}

This is a change in the USB1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [USB1](https://sugi.bio/atlas/gene/USB1/) |
| Protein change (HGVS p.) | p.Val71= |
| Coding change (HGVS c.) | c.213G>A |
| MANE Select transcript | [NM_024598](https://www.ncbi.nlm.nih.gov/nuccore/NM_024598) |
| dbSNP | [rs369515724](https://www.ncbi.nlm.nih.gov/snp/rs369515724/) |
| Variant type | single nucleotide variant |
| Location | chr16:58002593-58002593 (GRCh38) |
| ClinVar | [VCV769901](https://www.ncbi.nlm.nih.gov/clinvar/variation/769901/) |

**All HGVS expressions:** `LRG_352:g.6221G>A`, `LRG_352t1:c.213G>A`, `NC_000016.10:g.58002593G>A`, `NC_000016.9:g.58036497G>A`, `NG_027698.1:g.6221G>A`, `NM_001195302.2:c.213G>A`, `NM_001204911.2:c.213G>A`, `NM_001330568.2:c.60G>A`, `NM_001330569.2:c.213G>A`, `NM_024598.4:c.213G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.57) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -2.32, GERP -3.32 — fast-evolving / accelerated position
- CADD: **PHRED 15.75**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.57**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.57**.
- Pangolin: Δ**0.40** (gain), gain 0.40 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.055%** (amr) · FAF95 0.0402% · FAF99 0.0351% · 33/60,008 in the highest group · 94/1,613,938 alleles overall — ultra-rare (popmax 0.055%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.055% | 1,818 |
| East Asian | 0.0111% | 8,978 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,828 |
| European (non-Finnish) | 0.00441% | 22,693 |
| Finnish (not grpmax-eligible) | 0.00156% | 63,918 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**USB1** population constraint: LOEUF 1.016, pLI 3.1388e-05, missense-Z 0.5823; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **71** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 83.91, 65% of residues very-high.

**5 experimental structure(s)** (PDB): [4H7W](https://www.rcsb.org/structure/4H7W), [5V1M](https://www.rcsb.org/structure/5V1M), [6D2Z](https://www.rcsb.org/structure/6D2Z), [6D30](https://www.rcsb.org/structure/6D30), [6D31](https://www.rcsb.org/structure/6D31) — incl. mutant structure 6D2Z.

## What this gene does {#gene-function}

*Describes the biological roles of USB1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** USB1's established molecular role includes 3'-5'-RNA exonuclease activity. p.Val71= falls in the disordered region.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** 3'-5'-RNA exonuclease activity, poly(U)-specific exoribonuclease activity, producing 3' uridine cyclic phosphate ends.

**Biological process:** RNA splicing, snRNA 3'-end processing, U6 snRNA 3'-end processing.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-04-06.

**Submitter consensus:** conflicting (3 Likely benign, 1 Uncertain significance).

**Submission history:** 4 submissions (2021–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-08-02 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-04-06 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-13 |

**Reported phenotype names (ClinVar):** not provided, not specified, none provided, AllHighlyPenetrant.

## Similar variants {#similar}

Related USB1 variant pages (same residue, condition, or type): [USB1 p.Val71Met](/variant/usb1-p-val71met), [USB1 c.266-1G>A](/variant/usb1-c-266-minus-1g-a), [USB1 p.His208Arg](/variant/usb1-p-his208arg), [USB1 p.Ala106Ser](/variant/usb1-p-ala106ser), [USB1 p.Ala218Thr](/variant/usb1-p-ala218thr), [USB1 p.Ala218Val](/variant/usb1-p-ala218val), [USB1 p.Arg112Gln](/variant/usb1-p-arg112gln), [USB1 p.Arg112Trp](/variant/usb1-p-arg112trp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 769901). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*