Is AVIL p.Arg135Gln (c.404G>A) pathogenic?

AVIL p.Arg135Gln (c.404G>A) is classified Likely pathogenic in AVIL (ClinVar, Single submitter, 3 submitters; last evaluated 2023-07-10). AlphaMissense: likely benign (0.2229); Ultra-rare (popmax 0.092%, afr); Associated with nephrotic syndrome, type 21.

What condition is associated with AVIL p.Arg135Gln (c.404G>A)?

AVIL p.Arg135Gln (c.404G>A) is associated with nephrotic syndrome, type 21, steroid-resistant nephrotic syndrome (ClinVar).

How common is AVIL p.Arg135Gln (c.404G>A) in the general population?

AVIL p.Arg135Gln (c.404G>A) is ultra-rare (popmax 0.092%, afr) (gnomAD).

What do computational predictors say about AVIL p.Arg135Gln (c.404G>A)?

AlphaMissense predicts likely benign (score 0.2229) — an in-silico prediction, not a clinical call.

AVIL p.Arg135Gln

c.404G>A · rs138047529 · VCV684650

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2229 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.092%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

nephrotic syndrome, type 21

Computational evidence

Protein change
AlphaMissense	0.2229	likely benign ⚠ discordant with ClinVar
REVEL	0.564	indeterminate
SaProt	LLR -12.95	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 18 kb · p 9.4e-05 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.092% African / African-American · 69/75,022 alleles

Filtering AF 0.0745% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0682%

Overall 0.00545% 88/1,614,142 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.092%	1,087
Remaining individualsnot grpmax-eligible	0.0032%	31,253
Admixed American	0.00167%	60,014
European (non-Finnish)	0.00136%	73,752

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.Arg135Gln
Coding: c.404G>A
MANE Select: NM_006576
dbSNP: rs138047529
Type: single nucleotide variant
Location: chr12:57811062 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.82 · 1 PDB
Residue 135: a binding site; a UniProt-annotated variant site (in nphs21; inhibited actin bundling capacity; slightly decreased interaction with plce1; disrupted egf-induced diacylglycerol generation by plce1); the 'core' 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.Arg135Trp Uncertain significance ★ ⚠ same residue
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.Glu584Ter Likely pathogenic ★ same condition
AVIL p.Lys169Ter Likely pathogenic ★ same condition
AVIL c.66+9G>A Uncertain significance ★ 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-arg135gln (accessed [today's date]).

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