Is ASTN2 p.Arg375Cys (c.1123C>T) pathogenic?

ASTN2 p.Arg375Cys (c.1123C>T) is classified Likely benign in ASTN2 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-03-01). AlphaMissense: likely benign (0.145); Very rare (popmax 0.00952%, amr).

How common is ASTN2 p.Arg375Cys (c.1123C>T) in the general population?

ASTN2 p.Arg375Cys (c.1123C>T) is very rare (popmax 0.00952%, amr) (gnomAD).

What do computational predictors say about ASTN2 p.Arg375Cys (c.1123C>T)?

AlphaMissense predicts likely benign (score 0.145) — an in-silico prediction, not a clinical call.

ASTN2 p.Arg375Cys

c.1123C>T · rs371054320 · VCV3035665

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.145 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00952%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.145	likely benign
REVEL	0.144	moderately benign-leaning
SaProt	LLR -8.57	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 5.1	GERP 2.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 375 kb · p 0.43 · regional, not allelic
Overall
CADD	23.6	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 0.00952% Admixed American · 5/52,534 alleles

Filtering AF 0.00373% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00168% 23/1,367,404 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00952%	10,507
African / African-American	0.00443%	22,580
European (non-Finnish)	0.00147%	68,123

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.Arg375Cys
Coding: c.1123C>T
MANE Select: NM_001365068
dbSNP: rs371054320
Type: single nucleotide variant
Location: chr9:117141371 (GRCh38)
Gene constraint: LOEUF 0.473 · pLI 0.99 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 64.93 · 3 PDB
Residue 375: the 'disordered' region

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

Similar variants

TRIM32 p.Val375Gly Uncertain significance ★★ ⚠ same residue
TRIM32 p.Val375= 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

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-arg375cys (accessed [today's date]).

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