# NM_000374.5(UROD):c.270A>G (p.Val90=)

https://sugi.bio/variant/urod-p-val90

## Summary

**UROD p.Val90= (c.270A>G)** is classified **Likely benign** in UROD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-22). Ultra-rare (popmax 0.0637%, sas).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · ultra-rare (popmax 0.0637%, sas)

## For patients & families {#patients}

This is a change in the UROD gene that is classified as likely benign — not considered disease-causing, 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 | [UROD](https://sugi.bio/atlas/gene/UROD/) |
| Protein change (HGVS p.) | p.Val90= |
| Coding change (HGVS c.) | c.270A>G |
| MANE Select transcript | [NM_000374](https://www.ncbi.nlm.nih.gov/nuccore/NM_000374) |
| Variant type | single nucleotide variant |
| Location | chr1:45013348-45013348 (GRCh38) |
| ClinVar | [VCV4972129](https://www.ncbi.nlm.nih.gov/clinvar/variation/4972129/) |

**All HGVS expressions:** `LRG_1079:g.6191A>G`, `LRG_1079t1:c.270A>G`, `NC_000001.10:g.45479020A>G`, `NC_000001.11:g.45013348A>G`, `NG_007122.2:g.6191A>G`, `NG_033058.1:g.3008T>C`, `NM_000374.5:c.270A>G`, `NR_036510.2:n.332A>G`, `NR_158184.1:n.332A>G`, `NR_158185.1:n.282A>G`

## 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 2.02, GERP -0.655, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 8.71**. 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 (A>T, Δ0.24 acceptor gain), 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 **0.0637%** (sas) · FAF95 0.0505% · FAF99 0.0458% · 58/91,088 in the highest group · 76/1,614,110 alleles overall — ultra-rare (popmax 0.0637%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0637% | 1,570 |
| Middle Eastern | 0.0165% | 6,062 |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,500 |
| European (non-Finnish) | 0.00102% | 98,336 |

*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}

**UROD** population constraint: LOEUF 0.914, pLI 2.0406e-08, missense-Z 1.9357; ClinGen dosage — haploinsufficiency 2, triplosensitivity 0 (0–3 scale). *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):

- **UROD-related inherited porphyria** — Definitive (SD)

## Protein context {#protein}

Residue **90** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 96.90, 94% of residues very-high.

**19 experimental structure(s)** (PDB): [1JPH](https://www.rcsb.org/structure/1JPH), [1JPI](https://www.rcsb.org/structure/1JPI), [1JPK](https://www.rcsb.org/structure/1JPK), [1R3Q](https://www.rcsb.org/structure/1R3Q), [1R3R](https://www.rcsb.org/structure/1R3R), [1R3S](https://www.rcsb.org/structure/1R3S) — incl. mutant structure 1JPH.

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

*Describes the biological roles of UROD (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:** UROD's established molecular role includes uroporphyrinogen decarboxylase activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Heme biosynthesis](https://reactome.org/content/detail/R-HSA-189451) | curated |

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

**Molecular function:** uroporphyrinogen decarboxylase activity.

**Biological process:** porphyrin-containing compound metabolic process, obsolete protoporphyrinogen IX biosynthetic process, heme B biosynthetic process, porphyrin-containing compound catabolic process.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-11-22.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-22 |

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

## Same-residue context {#hotspot}

Residue **90** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [UROD p.Val90del](/variant/urod-p-val90del). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related UROD variant pages (same residue, condition, or type): [UROD p.Val90del](/variant/urod-p-val90del), [UROD c.636+1G>C](/variant/urod-c-636-plus-1g-c), [UROD p.Ala80Ser](/variant/urod-p-ala80ser), [UROD p.Arg142Ter](/variant/urod-p-arg142ter), [UROD p.Arg144Ter](/variant/urod-p-arg144ter), [UROD p.Arg193Pro](/variant/urod-p-arg193pro), [UROD p.Gln116Ter](/variant/urod-p-gln116ter), [UROD p.Gln206Ter](/variant/urod-p-gln206ter).

### 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 2026-07-14); 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 4972129). 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.*