Is ASTN2 p.Pro562Ser (c.1684C>T) pathogenic?

ASTN2 p.Pro562Ser (c.1684C>T) is classified Uncertain significance in ASTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-02). AlphaMissense: likely pathogenic (0.9502); Ultra-rare (popmax 0.0217%, amr).

How common is ASTN2 p.Pro562Ser (c.1684C>T) in the general population?

ASTN2 p.Pro562Ser (c.1684C>T) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about ASTN2 p.Pro562Ser (c.1684C>T)?

AlphaMissense predicts likely pathogenic (score 0.9502) — an in-silico prediction, not a clinical call.

ASTN2 p.Pro562Ser

c.1684C>T · rs578240181 · VCV2364669

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9502 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9502	likely pathogenic
REVEL	0.36	indeterminate
SaProt	LLR -5.45	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 314 kb · p 0.00026 · regional, not allelic
Overall
CADD	26.3	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 0.0217% Admixed American · 13/60,004 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0111%

Overall 0.0114% 184/1,614,022 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,616
European (non-Finnish)	0.0135%	7,421
Finnishnot grpmax-eligible	0.00937%	10,674
Remaining individualsnot grpmax-eligible	0.008%	12,501
African / African-American	0.00133%	75,032

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.Pro562Ser
Coding: c.1684C>T
MANE Select: NM_001365068
dbSNP: rs578240181
Type: single nucleotide variant
Location: chr9:116976181 (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.Gly562Asp Uncertain significance ★ ⚠ same residue
TRIM32 p.Gly562= Likely benign ★ same residue
TRIM32 p.Gly562fs Pathogenic ★ 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

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-pro562ser (accessed [today's date]).

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