# NM_001127255.2(NLRP7):c.308_315del (p.Pro103fs)

https://sugi.bio/variant/nlrp7-p-pro103fs

## Summary

**NLRP7 p.Pro103fs (c.308_315del)** is classified **Likely pathogenic** in NLRP7 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-08). Associated with NLRP7-related disorder.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the NLRP7 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to NLRP7-related disorder.

*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 | [NLRP7](https://sugi.bio/atlas/gene/NLRP7/) |
| Protein change (HGVS p.) | p.Pro103fs |
| Coding change (HGVS c.) | c.308_315del |
| MANE Select transcript | [NM_001127255](https://www.ncbi.nlm.nih.gov/nuccore/NM_001127255) |
| Variant type | Deletion |
| Location | chr19:54940968-54940975 (GRCh38) |
| ClinVar | [VCV4943962](https://www.ncbi.nlm.nih.gov/clinvar/variation/4943962/) |

**All HGVS expressions:** `NC_000019.10:g.54940968_54940975del`, `NC_000019.9:g.55452336_55452343del`, `NG_008056.1:g.11531_11538del`, `NG_008056.2:g.30269_30276del`, `NM_001127255.2:c.308_315del`, `NM_001405531.1:c.308_315del`, `NM_139176.4:c.308_315del`, `NM_206828.4:c.308_315del`

## 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 -1.118, GERP 1.45 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.959, pLI 1.8044e-18. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 11**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**NLRP7** population constraint: LOEUF 0.959, pLI 1.8044e-18, missense-Z 0.2054. *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 82.25, 41% of residues very-high.

**3 experimental structure(s)** (PDB): [2KM6](https://www.rcsb.org/structure/2KM6), [9LQ2](https://www.rcsb.org/structure/9LQ2), [9LQ4](https://www.rcsb.org/structure/9LQ4).

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

*Describes the biological roles of NLRP7 (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:** NLRP7's established molecular role includes aspartic-type endopeptidase inhibitor activity.


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

**Molecular function:** aspartic-type endopeptidase inhibitor activity, interleukin-1 binding, identical protein binding, caspase binding.

**Biological process:** negative regulation of protein processing, negative regulation of interleukin-1 beta production, cellular response to lipopolysaccharide, cellular response to interleukin-1, negative regulation of cytokine production involved in inflammatory response.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-06-08.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-06-08 |

## Associated conditions {#conditions}

[NLRP7-related disorder](https://sugi.bio/atlas/disease/nlrp7-related-disorder/).

**Reported phenotype names (ClinVar):** NLRP7-related disorder, NLRP7-related condition.

## Similar variants {#similar}

Related NLRP7 variant pages (same residue, condition, or type): [NLRP7 p.Glu113Glyfs](/variant/nlrp7-p-glu113glyfs), [NLRP7 p.Met427Thr](/variant/nlrp7-p-met427thr), [NLRP7 p.Lys619Asnfs](/variant/nlrp7-p-lys619asnfs).

### 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 4943962). 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.*