Is ASTN2 p.Pro852Ser (c.2554C>T) pathogenic?

ASTN2 p.Pro852Ser (c.2554C>T) is classified Uncertain significance in ASTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-06). AlphaMissense: likely pathogenic (0.8785); Ultra-rare (popmax 0.0138%, amr).

How common is ASTN2 p.Pro852Ser (c.2554C>T) in the general population?

ASTN2 p.Pro852Ser (c.2554C>T) is ultra-rare (popmax 0.0138%, amr) (gnomAD).

What do computational predictors say about ASTN2 p.Pro852Ser (c.2554C>T)?

AlphaMissense predicts likely pathogenic (score 0.8785) — an in-silico prediction, not a clinical call.

ASTN2 p.Pro852Ser

c.2554C>T · rs200102968 · VCV2568821

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8785 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0138%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8785	likely pathogenic
REVEL	0.338	indeterminate
SaProt	LLR -10.64	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 314 kb · p 0.00026 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0138% Admixed American · 8/57,820 alleles

Filtering AF 0.00683% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00498%

Overall 0.00639% 102/1,596,278 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.25%	400
Remaining individualsnot grpmax-eligible	0.0194%	5,150
Admixed Americangrpmax	0.0138%	7,228
European (non-Finnish)	0.000769%	130,092

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro852Ser
Coding: c.2554C>T
MANE Select: NM_001365068
dbSNP: rs200102968
Type: single nucleotide variant
Location: chr9:116729064 (GRCh38)
Gene constraint: LOEUF 0.473 · pLI 0.99 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 64.93 · 3 PDB
Residue 852: a disulfide bond

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

Similar variants

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
TRIM32 p.Ala126Val 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-pro852ser (accessed [today's date]).

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