Is AVIL p.Phe656fs (c.1964dup) pathogenic?

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.

What condition is associated with AVIL p.Phe656fs (c.1964dup)?

AVIL p.Phe656fs (c.1964dup) is associated with nephrotic syndrome, type 21, steroid-resistant nephrotic syndrome (ClinVar).

How common is AVIL p.Phe656fs (c.1964dup) in the general population?

AVIL p.Phe656fs (c.1964dup) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

AVIL p.Phe656fs

c.1964dup · rs753128516 · VCV684651

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Conditions

nephrotic syndrome, type 21

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 17 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.3	GERP -3.8
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0495% Middle Eastern · 3/6,056 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0095%

Overall 0.0101% 163/1,609,454 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,019
South Asian	0.0144%	6,945
European (non-Finnish)	0.0117%	8,533
Ashkenazi Jewishnot grpmax-eligible	0.0102%	9,816
Remaining individualsnot grpmax-eligible	0.00641%	15,589
African / African-American	0.00267%	37,502

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: AVIL
Protein: p.Phe656fs
Coding: c.1964dup
MANE Select: NM_006576
dbSNP: rs753128516
Type: Duplication
Location: chr12:57802346 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.82 · 1 PDB
Residue 656: the 'core' region; the 'required for interaction with f-actin' region

Full AVIL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephrotic syndrome, type 21 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: steroid-resistant nephrotic syndrome

Similar variants

AVIL p.Leu272fs Uncertain significance ★ same condition
AVIL p.Arg199Ter Likely pathogenic ★★ same condition
AVIL p.Asn777Lys Uncertain significance ★★ ⚠ same condition
AVIL p.Ile250Thr Uncertain significance ★★ ⚠ same condition
AVIL p.Lys204Glu Benign/Likely benign ★★ same condition
AVIL p.Arg135Gln Likely pathogenic ★ ⚠ same condition
AVIL p.Asp41fs Likely pathogenic ★ same condition
AVIL p.Glu584Ter Likely pathogenic ★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/avil-p-phe656fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown