# NM_006576.4(AVIL):c.1964dup (p.Phe656fs)

https://sugi.bio/variant/avil-p-phe656fs

## Summary

**AVIL p.Phe656fs (c.1964dup)** is classified **Conflicting classifications of pathogenicity** in AVIL (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-04). Ultra-rare (popmax 0.0495%, mid); Associated with nephrotic syndrome, type 21.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs753128516 · 5 submitters · 2 linked conditions · ultra-rare (popmax 0.0495%, mid)

## For patients & families {#patients}

This is a change in the AVIL gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 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.Phe656fs |
| Coding change (HGVS c.) | c.1964dup |
| MANE Select transcript | [NM_006576](https://www.ncbi.nlm.nih.gov/nuccore/NM_006576) |
| dbSNP | [rs753128516](https://www.ncbi.nlm.nih.gov/snp/rs753128516/) |
| Variant type | Duplication |
| Location | chr12:57802346-57802347 (GRCh38) |
| ClinVar | [VCV684651](https://www.ncbi.nlm.nih.gov/clinvar/variation/684651/) |

**All HGVS expressions:** `NC_000012.11:g.58196130dup`, `NC_000012.12:g.57802347dup`, `NG_016971.1:g.24603dup`, `NM_001172697.2:c.572-208dup`, `NM_006576.3:c.1964dupT`, `NM_006576.4:c.1964dup`, `NM_006576.4:c.1964dupT`

## 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 -1.255, GERP -3.81 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.81, pLI 6.5982e-17. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 17 of 20**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 33.0**. 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** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0495%** (mid) · FAF95 0.0134% · FAF99 0.0095% · 3/6,056 in the highest group · 163/1,609,454 alleles overall — ultra-rare (popmax 0.0495%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0495% | 2,019 |
| South Asian | 0.0144% | 6,945 |
| European (non-Finnish) | 0.0117% | 8,533 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0102% | 9,816 |
| Remaining individuals (not grpmax-eligible) | 0.00641% | 15,589 |
| African / African-American | 0.00267% | 37,502 |

*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 **656** lies in the 'core' region; the 'required for interaction with f-actin' 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.Phe656fs 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-04.

**Submitter consensus:** conflicting (3 Pathogenic, 1 Uncertain significance, 1 Likely pathogenic).

**Submission history:** 5 submissions (2017–2025); classifications have differed over time.

### 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 |
| MGZ Medical Genetics Center | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-08-25 |
| First Genomix Gene Laboratory, Genetic Diagnostics Department | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-01-13 |
| Dasa | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-04 |

## 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, not provided, none provided.

## Similar variants {#similar}

Related AVIL variant pages (same residue, condition, or type): [AVIL p.Leu272fs](/variant/avil-p-leu272fs), [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.Asp41fs](/variant/avil-p-asp41fs), [AVIL p.Glu584Ter](/variant/avil-p-glu584ter).

### 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 684651). 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.*