Is ASTN2 p.Ile131Phe (c.391A>T) pathogenic?

ASTN2 p.Ile131Phe (c.391A>T) is classified Uncertain significance in ASTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-30). AlphaMissense: ambiguous (0.4123); Ultra-rare (popmax 0.0252%, eas).

How common is ASTN2 p.Ile131Phe (c.391A>T) in the general population?

ASTN2 p.Ile131Phe (c.391A>T) is ultra-rare (popmax 0.0252%, eas) (gnomAD).

What do computational predictors say about ASTN2 p.Ile131Phe (c.391A>T)?

AlphaMissense predicts ambiguous (score 0.4123) — an in-silico prediction, not a clinical call.

ASTN2 p.Ile131Phe

c.391A>T · rs747752145 · VCV2600522

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4123 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0252%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4123	ambiguous
REVEL	0.132	moderately benign-leaning
SaProt	LLR -5.91	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 1.6, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 375 kb · p 0.43 · regional, not allelic
Overall
CADD	22.6	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 0.0252% East Asian · 11/43,674 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.000685% 11/1,604,770 alleles · ultra-rare

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: ASTN2
Protein: p.Ile131Phe
Coding: c.391A>T
MANE Select: NM_001365068
dbSNP: rs747752145
Type: single nucleotide variant
Location: chr9:117414548 (GRCh38)
Gene constraint: LOEUF 0.473 · pLI 0.99 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 64.93 · 3 PDB

Full ASTN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRIM32 p.Pro131= Likely benign ★ same residue
TRIM32 p.Arg500Ter Pathogenic/Likely pathogenic ★★ same type
TRIM32 p.Asp487Asn Pathogenic ★★ same type
TRIM32 p.Lys401Ter Pathogenic ★★ same type
TRIM32 p.Tyr226Ter Pathogenic/Likely pathogenic ★★ same type
TRIM32 p.Tyr528Ter Likely pathogenic ★★ same type
ASTN2 p.Val880Gly Uncertain significance ★★ ⚠ same type
TRIM32 c.*152T>G Uncertain significance ★★ same type

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/astn2-p-ile131phe (accessed [today's date]).

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