# NM_020120.4(UGGT1):c.523C>T (p.Pro175Ser)

https://sugi.bio/variant/uggt1-p-pro175ser

## Summary

**UGGT1 p.Pro175Ser (c.523C>T)** is classified **Uncertain significance** in UGGT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-11). AlphaMissense: likely benign (0.1039); Ultra-rare (popmax 0.0271%, eas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs928402338 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0271%, eas)

## For patients & families {#patients}

This is a change in the UGGT1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [UGGT1](https://sugi.bio/atlas/gene/UGGT1/) |
| Protein change (HGVS p.) | p.Pro175Ser |
| Coding change (HGVS c.) | c.523C>T |
| MANE Select transcript | [NM_020120](https://www.ncbi.nlm.nih.gov/nuccore/NM_020120) |
| dbSNP | [rs928402338](https://www.ncbi.nlm.nih.gov/snp/rs928402338/) |
| Variant type | single nucleotide variant |
| Location | chr2:128113085-128113085 (GRCh38) |
| ClinVar | [VCV2610693](https://www.ncbi.nlm.nih.gov/clinvar/variation/2610693/) |

**All HGVS expressions:** `NC_000002.11:g.128870659C>T`, `NC_000002.12:g.128113085C>T`, `NM_020120.4:c.523C>T`, `NR_027671.3:n.862C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1039)
- REVEL 0.163 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.411 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.23) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.995, GERP 1.72, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.5**. 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.*
- Regional missense constraint: **o/e 0.99** across the covering region of the MANE Select transcript (128,104,003–128,170,334), spanning 66,331 bp. Chi-square p 0.86. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.23**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 22 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.0271%** (eas) · FAF95 0.0152% · FAF99 0.0117% · 11/40,542 in the highest group · 19/1,482,560 alleles overall — ultra-rare (popmax 0.0271%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0271% | 3,686 |
| Remaining individuals (not grpmax-eligible) | 0.00535% | 18,687 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00392% | 25,514 |
| Admixed American | 0.0023% | 43,558 |
| European (non-Finnish) | 0.00027% | 369,917 |

*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}

**UGGT1** population constraint: LOEUF 0.617, pLI 7.4921e-11, missense-Z 2.2695. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 83.97, 43% of residues very-high.

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

*Describes the biological roles of UGGT1 (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:** UGGT1's established molecular role includes UDP-glucose:glycoprotein glucosyltransferase activity.


### Pathways affected {#pathways}

UGGT1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [ER Quality Control Compartment (ERQC)](https://reactome.org/content/detail/R-HSA-901032) | curated |

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

**Molecular function:** UDP-glucose:glycoprotein glucosyltransferase activity, obsolete unfolded protein binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-07-11.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-07-11 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related UGGT1 variant pages (same residue, condition, or type): [UGGT1 p.Glu918Lys](/variant/uggt1-p-glu918lys), [UGGT1 p.Pro1126Leu](/variant/uggt1-p-pro1126leu), [UGGT1 c.278-9C>T](/variant/uggt1-c-278-minus-9c-t), [UGGT1 c.3025-4C>T](/variant/uggt1-c-3025-minus-4c-t), [UGGT1 c.4643-8T>G](/variant/uggt1-c-4643-minus-8t-g), [UGGT1 p.Ala669Val](/variant/uggt1-p-ala669val), [UGGT1 p.Asn1139Ser](/variant/uggt1-p-asn1139ser), [UGGT1 p.Glu422=](/variant/uggt1-p-glu422).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2610693). 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.*