Is ASTN2 p.Val175Ile (c.523G>A) pathogenic?

ASTN2 p.Val175Ile (c.523G>A) is classified Uncertain significance in ASTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-22). AlphaMissense: likely benign (0.1092); Ultra-rare (popmax 0.0231%, sas).

How common is ASTN2 p.Val175Ile (c.523G>A) in the general population?

ASTN2 p.Val175Ile (c.523G>A) is ultra-rare (popmax 0.0231%, sas) (gnomAD).

What do computational predictors say about ASTN2 p.Val175Ile (c.523G>A)?

AlphaMissense predicts likely benign (score 0.1092) — an in-silico prediction, not a clinical call.

ASTN2 p.Val175Ile

c.523G>A · VCV4157546

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1092 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0231%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1092	likely benign
REVEL	0.191	benign-leaning
SaProt	LLR -6.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 0.94, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 375 kb · p 0.43 · regional, not allelic
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0231% South Asian · 21/91,072 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0129%

Overall 0.00396% 64/1,614,146 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0231%	4,337
East Asian	0.0111%	8,975
Admixed American	0.00666%	15,006
Remaining individualsnot grpmax-eligible	0.0064%	15,627
Finnishnot grpmax-eligible	0.00312%	32,017
European (non-Finnish)	0.00229%	43,704
African / African-American	0.00133%	75,056

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.Val175Ile
Coding: c.523G>A
MANE Select: NM_001365068
Type: single nucleotide variant
Location: chr9:117291433 (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.Lys175Arg Uncertain significance ★★ ⚠ same residue
TRIM32 p.Lys175Gln Uncertain significance ★ ⚠ 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

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-val175ile (accessed [today's date]).

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