# NM_020167.5(NMUR2):c.997C>T (p.Arg333Cys)

https://sugi.bio/variant/nmur2-p-arg333cys

## Summary

**NMUR2 p.Arg333Cys (c.997C>T)** is classified **Uncertain significance** in NMUR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-20). AlphaMissense: likely benign (0.3053); Ultra-rare (popmax 0.0334%, eas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs368160909 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0334%, eas)

## For patients & families {#patients}

This is a change in the NMUR2 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 | [NMUR2](https://sugi.bio/atlas/gene/NMUR2/) |
| Protein change (HGVS p.) | p.Arg333Cys |
| Coding change (HGVS c.) | c.997C>T |
| MANE Select transcript | [NM_020167](https://www.ncbi.nlm.nih.gov/nuccore/NM_020167) |
| dbSNP | [rs368160909](https://www.ncbi.nlm.nih.gov/snp/rs368160909/) |
| Variant type | single nucleotide variant |
| Location | chr5:152392442-152392442 (GRCh38) |
| ClinVar | [VCV2238869](https://www.ncbi.nlm.nih.gov/clinvar/variation/2238869/) |

**All HGVS expressions:** `NC_000005.10:g.152392442G>A`, `NC_000005.9:g.151772003G>A`, `NM_020167.5:c.997C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.3053)
- REVEL 0.25 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -11.129 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense and REVEL do not
- Conservation: phyloP 7.117, GERP 1.73, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 28.6**. 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 1.04** across the covering region of the MANE Select transcript (152,392,194–152,405,113), spanning 12,919 bp. Chi-square p 0.37. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.28 acceptor 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 **0.0334%** (eas) · FAF95 0.0206% · FAF99 0.0166% · 15/44,886 in the highest group · 57/1,613,890 alleles overall — ultra-rare (popmax 0.0334%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0334% | 2,992 |
| Middle Eastern | 0.0329% | 3,042 |
| African / African-American | 0.0174% | 5,762 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,245 |
| South Asian | 0.0022% | 45,538 |
| European (non-Finnish) | 0.00186% | 53,633 |
| Admixed American | 0.00167% | 59,984 |

*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}

**NMUR2** population constraint: LOEUF 1.327, pLI 4.2504e-07, missense-Z 0.12467. *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 **333** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 79.92, 51% of residues very-high.

**3 experimental structure(s)** (PDB): [7W55](https://www.rcsb.org/structure/7W55), [7W57](https://www.rcsb.org/structure/7W57), [7XK8](https://www.rcsb.org/structure/7XK8).

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

*Describes the biological roles of NMUR2 (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:** NMUR2's established molecular role includes neuromedin U receptor activity.


### Pathways affected {#pathways}

NMUR2 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [G alpha (i) signalling events](https://reactome.org/content/detail/R-HSA-418594) | curated |
| [G alpha (q) signalling events](https://reactome.org/content/detail/R-HSA-416476) | curated |
| [Peptide ligand-binding receptors](https://reactome.org/content/detail/R-HSA-375276) | curated |

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

**Molecular function:** neuromedin U receptor activity, intracellularly calcium-gated chloride channel activity, GTP binding, neuromedin U binding.

**Biological process:** phospholipase C-activating G protein-coupled receptor signaling pathway, neuropeptide signaling pathway, arachidonate secretion.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-07-20.

**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 | 2021-07-20 |

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

## Similar variants {#similar}

Related NMUR2 variant pages (same residue, condition, or type): [NMUR2 p.Ala124Val](/variant/nmur2-p-ala124val), [NMUR2 p.Ala132Val](/variant/nmur2-p-ala132val), [NMUR2 p.Ala147Thr](/variant/nmur2-p-ala147thr), [NMUR2 p.Ala154Val](/variant/nmur2-p-ala154val), [NMUR2 p.Ala395Glu](/variant/nmur2-p-ala395glu), [NMUR2 p.Arg108His](/variant/nmur2-p-arg108his), [NMUR2 p.Arg153Leu](/variant/nmur2-p-arg153leu), [NMUR2 p.Arg162Trp](/variant/nmur2-p-arg162trp).

### 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 2238869). 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.*