# NM_006576.4(AVIL):c.1337G>A (p.Arg446His)

https://sugi.bio/variant/avil-p-arg446his

## Summary

**AVIL p.Arg446His (c.1337G>A)** is classified **Pathogenic** in AVIL (ClinVar, No assertion criteria, 2 submitters; last evaluated 2019-09-25). AlphaMissense: likely benign (0.0937); Very rare (popmax 0.00549%, sas); Associated with nephrotic syndrome, type 21.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs1334894971 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00549%, sas)

## For patients & families {#patients}

This is a change in the AVIL gene that is reported as disease-causing, though the computational evidence is not fully concordant, submitted by 2 submitters, and is linked to nephrotic syndrome, type 21.

*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/0027944/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AVIL](https://sugi.bio/atlas/gene/AVIL/) |
| Protein change (HGVS p.) | p.Arg446His |
| Coding change (HGVS c.) | c.1337G>A |
| MANE Select transcript | [NM_006576](https://www.ncbi.nlm.nih.gov/nuccore/NM_006576) |
| dbSNP | [rs1334894971](https://www.ncbi.nlm.nih.gov/snp/rs1334894971/) |
| Variant type | single nucleotide variant |
| Location | chr12:57807485-57807485 (GRCh38) |
| ClinVar | [VCV684649](https://www.ncbi.nlm.nih.gov/clinvar/variation/684649/) |

**All HGVS expressions:** `NC_000012.11:g.58201268C>T`, `NC_000012.12:g.57807485C>T`, `NM_006576.4:c.1337G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0937) — ⚠ discordant with the pathogenic call
- REVEL 0.265 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.304 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.413, GERP 2.34, phastCons 1 — weakly conserved position
- CADD: **PHRED 26.2**. 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 0.88** across the covering region of the MANE Select transcript (57,797,885–57,816,040), spanning 18,155 bp. Chi-square p 9.4e-05. 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 (C>G, Δ0.33 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 **0.00549%** (sas) · FAF95 0.0021% · FAF99 0.00136% · 5/91,094 in the highest group · 19/1,614,130 alleles overall — very rare (popmax 0.00549%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00549% | 18,219 |
| Admixed American | 0.005% | 20,005 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,830 |
| European (non-Finnish) | 0.000678% | 147,507 |

*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}

**AVIL** population constraint: LOEUF 0.81, pLI 6.5982e-17, missense-Z 2.0302. *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):

- **nephrotic syndrome, type 21** — Limited (AR)

## Protein context {#protein}

Residue **446** lies in a UniProt-annotated variant site (in nphs21; uncertain significance); the 'core' region.

AlphaFold model confidence (whole protein): pLDDT 79.82, 24% of residues very-high.

**1 experimental structure(s)** (PDB): [1UND](https://www.rcsb.org/structure/1UND).

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

*Describes the biological roles of AVIL (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:** AVIL's established molecular role includes actin filament binding. p.Arg446His falls in the core region.


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

**Molecular function:** actin filament binding, Arp2/3 complex binding.

**Biological process:** actin filament organization, positive regulation of lamellipodium assembly, cilium assembly, regulation of diacylglycerol biosynthetic process.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-09-25.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2017–2019); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Yale Center for Mendelian Genomics, Yale University | Pathogenic | no assertion criteria provided | literature only | 2017-10-23 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2019-09-25 |

## Associated conditions {#conditions}

[nephrotic syndrome, type 21](https://sugi.bio/atlas/disease/nephrotic-syndrome-type-21/), [steroid-resistant nephrotic syndrome](https://sugi.bio/atlas/disease/steroid-resistant-nephrotic-syndrome/).

**Reported phenotype names (ClinVar):** Nephrotic syndrome, type 21, Steroid-resistant nephrotic syndrome.

## Similar variants {#similar}

Related AVIL variant pages (same residue, condition, or type): [AVIL p.Arg199Ter](/variant/avil-p-arg199ter), [AVIL p.Asn777Lys](/variant/avil-p-asn777lys), [AVIL p.Ile250Thr](/variant/avil-p-ile250thr), [AVIL p.Lys204Glu](/variant/avil-p-lys204glu), [AVIL p.Arg135Gln](/variant/avil-p-arg135gln), [AVIL p.Glu584Ter](/variant/avil-p-glu584ter), [AVIL p.Lys169Ter](/variant/avil-p-lys169ter), [AVIL c.66+9G>A](/variant/avil-c-66-plus-9g-a).

### 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 684649). 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.*