# NM_080911.3(UNG):c.522G>A (p.Pro174=)

https://sugi.bio/variant/ung-p-pro174

## Summary

**UNG p.Pro174= (c.522G>A)** is classified **Likely benign** in UNG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-05). Ultra-rare (popmax 0.0666%, afr); Associated with hyper-IgM syndrome type 5.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs148037258 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0666%, afr)

## For patients & families {#patients}

This is a change in the UNG gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to hyper-IgM syndrome type 5.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010581/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [UNG](https://sugi.bio/atlas/gene/UNG/) |
| Protein change (HGVS p.) | p.Pro174= |
| Coding change (HGVS c.) | c.522G>A |
| MANE Select transcript | [NM_080911](https://www.ncbi.nlm.nih.gov/nuccore/NM_080911) |
| dbSNP | [rs148037258](https://www.ncbi.nlm.nih.gov/snp/rs148037258/) |
| Variant type | single nucleotide variant |
| Location | chr12:109101988-109101988 (GRCh38) |
| ClinVar | [VCV1094386](https://www.ncbi.nlm.nih.gov/clinvar/variation/1094386/) |

**All HGVS expressions:** `LRG_124:g.9379G>A`, `NC_000012.11:g.109539793G>A`, `NC_000012.12:g.109101988G>A`, `NG_007284.1:g.9379G>A`, `NM_003362.4:c.495G>A`, `NM_080911.3:c.522G>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 (below), not from a missing predictor score.
- Conservation: phyloP -2.297, GERP -9.67 — fast-evolving / accelerated position
- CADD: **PHRED 4.265**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.24 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0666%** (afr) · FAF95 0.0519% · FAF99 0.0467% · 50/75,036 in the highest group · 70/1,613,842 alleles overall — ultra-rare (popmax 0.0666%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0666% | 1,501 |
| Middle Eastern | 0.0168% | 5,962 |
| East Asian | 0.0134% | 7,480 |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,497 |
| Admixed American | 0.005% | 20,001 |
| South Asian | 0.0022% | 45,535 |
| European (non-Finnish) | 0.000254% | 393,298 |

*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}

**UNG** population constraint: LOEUF 1.22, pLI 2.5181e-11, missense-Z 0.31457. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **hyper-IgM syndrome type 5** — Moderate (AR)

## Protein context {#protein}

Residue **174** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 86.52, 75% of residues very-high.

**24 experimental structure(s)** (PDB): [1AKZ](https://www.rcsb.org/structure/1AKZ), [1DPU](https://www.rcsb.org/structure/1DPU), [1EMH](https://www.rcsb.org/structure/1EMH), [1EMJ](https://www.rcsb.org/structure/1EMJ), [1Q3F](https://www.rcsb.org/structure/1Q3F), [1SSP](https://www.rcsb.org/structure/1SSP) — incl. mutant structure 3TKB.

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

*Describes the biological roles of UNG (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:** UNG's established molecular role includes damaged DNA binding.


### Pathways affected {#pathways}

UNG participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Chromatin modifications during the maternal to zygotic transition (MZT)](https://reactome.org/content/detail/R-HSA-9821002) | other |
| [Cleavage of the damaged pyrimidine ](https://reactome.org/content/detail/R-HSA-110329) | other |
| [Displacement of DNA glycosylase by APEX1](https://reactome.org/content/detail/R-HSA-110357) | other |
| [Recognition and association of DNA glycosylase with site containing an affected pyrimidine](https://reactome.org/content/detail/R-HSA-110328) | other |

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

**Molecular function:** damaged DNA binding, uracil DNA N-glycosylase activity, ribosomal small subunit binding.

**Biological process:** base-excision repair, base-excision repair, AP site formation via deaminated base removal.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-05.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2023–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-05 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-12-11 |

## Associated conditions {#conditions}

[hyper-IgM syndrome type 5](https://sugi.bio/atlas/disease/hyper-igm-syndrome-type-5/).

**Reported phenotype names (ClinVar):** Hyper-IgM syndrome type 5, not specified, Hyper-IgM Immunodeficiency Syndrome, Type 5, AllHighlyPenetrant.

## Similar variants {#similar}

Related UNG variant pages (same residue, condition, or type): [UNG p.Pro174Leu](/variant/ung-p-pro174leu), [UNG c.623-9T>A](/variant/ung-c-623-minus-9t-a), [UNG c.801+5G>A](/variant/ung-c-801-plus-5g-a), [UNG p.Ala21Thr](/variant/ung-p-ala21thr), [UNG p.Ala87Val](/variant/ung-p-ala87val), [UNG p.Arg122Ser](/variant/ung-p-arg122ser), [UNG p.Arg269Trp](/variant/ung-p-arg269trp), [UNG p.Asn77Lys](/variant/ung-p-asn77lys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1094386). 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.*