Is AVIL p.Arg446His (c.1337G>A) pathogenic?

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.

What condition is associated with AVIL p.Arg446His (c.1337G>A)?

AVIL p.Arg446His (c.1337G>A) is associated with nephrotic syndrome, type 21, steroid-resistant nephrotic syndrome (ClinVar).

How common is AVIL p.Arg446His (c.1337G>A) in the general population?

AVIL p.Arg446His (c.1337G>A) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about AVIL p.Arg446His (c.1337G>A)?

AlphaMissense predicts likely benign (score 0.0937) — an in-silico prediction, not a clinical call.

AVIL p.Arg446His

c.1337G>A · rs1334894971 · VCV684649

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0937 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephrotic syndrome, type 21

Computational evidence

Protein change
AlphaMissense	0.0937	likely benign ⚠ discordant with ClinVar
REVEL	0.265	benign-leaning
SaProt	LLR -9.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.33 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.4	GERP 2.3, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 18 kb · p 9.4e-05 · regional, not allelic
Overall
CADD	26.2	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 0.00549% South Asian · 5/91,094 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00118% 19/1,614,130 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,219
Admixed American	0.005%	20,005
Remaining individualsnot grpmax-eligible	0.0048%	20,830
European (non-Finnish)	0.000678%	147,507

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.Arg446His
Coding: c.1337G>A
MANE Select: NM_006576
dbSNP: rs1334894971
Type: single nucleotide variant
Location: chr12:57807485 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.82 · 1 PDB
Residue 446: a UniProt-annotated variant site (in nphs21; uncertain significance); 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.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.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-arg446his (accessed [today's date]).

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