# NM_000490.5(AVP):c.20C>T (p.Pro7Leu)

https://sugi.bio/variant/avp-p-pro7leu

## Summary

**AVP p.Pro7Leu (c.20C>T)** is classified **Pathogenic** in AVP (ClinVar, No assertion criteria, 1 submitter; last evaluated 2004-09-01). AlphaMissense: likely benign (0.0958); Absent from gnomAD v4.1; Associated with Diabetes insipidus, neurohypophyseal, autosomal recessive.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs121964892 · 1 submitter · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the AVP gene that is reported as disease-causing, though the computational evidence is not fully concordant, submitted by 1 submitter, and is linked to Diabetes insipidus, neurohypophyseal, autosomal recessive.

*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 | [AVP](https://sugi.bio/atlas/gene/AVP/) |
| Protein change (HGVS p.) | p.Pro7Leu |
| Coding change (HGVS c.) | c.20C>T |
| MANE Select transcript | [NM_001243133](https://www.ncbi.nlm.nih.gov/nuccore/NM_001243133) (variant reported on NM_000490) |
| dbSNP | [rs121964892](https://www.ncbi.nlm.nih.gov/snp/rs121964892/) |
| Variant type | single nucleotide variant |
| Location | chr20:3084655-3084655 (GRCh38) |
| ClinVar | [VCV12219](https://www.ncbi.nlm.nih.gov/clinvar/variation/12219/) |

**All HGVS expressions:** `LRG_715:g.5070C>T`, `LRG_715t1:c.20C>T`, `NC_000020.10:g.3065301G>A`, `NC_000020.11:g.3084655G>A`, `NG_008663.1:g.5070C>T`, `NM_000490.5:c.20C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.0958) — ⚠ discordant with the pathogenic call
- REVEL 0.235 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -2.159 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 3.27, GERP 0.07, phastCons 0.996 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 16.87**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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.*

## Protein context {#protein}

Residue **7** lies in the pyrin domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 81.16, 47% of residues very-high.

**27 experimental structure(s)** (PDB): [2NAQ](https://www.rcsb.org/structure/2NAQ), [3QF2](https://www.rcsb.org/structure/3QF2), [6NPY](https://www.rcsb.org/structure/6NPY), [7ALV](https://www.rcsb.org/structure/7ALV), [7PZC](https://www.rcsb.org/structure/7PZC), [7PZD](https://www.rcsb.org/structure/7PZD).

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

*Describes the biological roles of AVP (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:** AVP's established molecular role includes ATP binding. p.Pro7Leu falls in the pyrin domain. In Reactome, AVP is annotated in disease pathway(s) including **SARS-CoV-1 activates/modulates innate immune responses**, **SARS-CoV-2 activates/modulates innate and adaptive immune responses**.

**Disease mechanism (Reactome):** AVP loss or alteration is curated in [SARS-CoV-1 activates/modulates innate immune responses](https://reactome.org/content/detail/R-HSA-9692916), [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671), [Purinergic signaling in leishmaniasis infection](https://reactome.org/content/detail/R-HSA-9660826).

### Pathways affected {#pathways}

AVP participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [SARS-CoV-1 activates/modulates innate immune responses](https://reactome.org/content/detail/R-HSA-9692916) | curated |
| ⚕ [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671) | curated |
| ⚕ [Purinergic signaling in leishmaniasis infection](https://reactome.org/content/detail/R-HSA-9660826) | electronic |
| [Metalloprotease DUBs](https://reactome.org/content/detail/R-HSA-5689901) | curated |
| [Cytoprotection by HMOX1](https://reactome.org/content/detail/R-HSA-9707564) | electronic |
| [The NLRP3 inflammasome](https://reactome.org/content/detail/R-HSA-844456) | electronic |

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

**Molecular function:** ATP binding, ATP hydrolysis activity, protein-macromolecule adaptor activity, signaling adaptor activity, identical protein binding, ADP binding.

**Biological process:** negative regulation of acute inflammatory response, inflammatory response, detection of biotic stimulus, negative regulation of interleukin-1 beta production, positive regulation of interleukin-1 beta production, NLRP3 inflammasome complex assembly.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2004-09-01.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2004-09-01 |

## Associated conditions {#conditions}

[Diabetes insipidus, neurohypophyseal, autosomal recessive](https://sugi.bio/atlas/disease/diabetes-insipidus-neurohypophyseal-autosomal-recessive/).

**Reported phenotype names (ClinVar):** Diabetes insipidus, neurohypophyseal, autosomal recessive.

## Similar variants {#similar}

Related AVP variant pages (same residue, condition, or type): [AVP p.Pro7=](/variant/avp-p-pro7), [AVP p.Ala19Thr](/variant/avp-p-ala19thr), [AVP p.Cys92Tyr](/variant/avp-p-cys92tyr), [AVP p.Glu108Ter](/variant/avp-p-glu108ter), [AVP p.Gly54Arg](/variant/avp-p-gly54arg), [AVP p.Gly96Asp](/variant/avp-p-gly96asp), [AVP p.Ser87Phe](/variant/avp-p-ser87phe), [NLRP3 p.Ala352Thr](/variant/nlrp3-p-ala352thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 12219). 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.*