Is CLSTN2 p.Gln433Arg (c.1298A>G) pathogenic?

CLSTN2 p.Gln433Arg (c.1298A>G) is classified Uncertain significance in CLSTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-10). AlphaMissense: likely benign (0.0969); Absent from gnomAD v4.1.

How common is CLSTN2 p.Gln433Arg (c.1298A>G) in the general population?

CLSTN2 p.Gln433Arg (c.1298A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLSTN2 p.Gln433Arg (c.1298A>G)?

AlphaMissense predicts likely benign (score 0.0969) — an in-silico prediction, not a clinical call.

CLSTN2 p.Gln433Arg

c.1298A>G · VCV3834186

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0969 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0969	likely benign
REVEL	0.486	indeterminate
SaProt	LLR -6.74	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 631 kb · p 0.026 · regional, not allelic
Overall
CADD	25.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLSTN2
Protein: p.Gln433Arg
Coding: c.1298A>G
MANE Select: NM_022131
Type: single nucleotide variant
Location: chr3:140466685 (GRCh38)
Gene constraint: LOEUF 0.578 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.46

Full CLSTN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLSTN2 c.233-8T>G Benign ★★ same type
CLSTN2 p.Gly776= Benign ★★ same type
CLSTN2 p.Ile124= Benign ★★ same type
CLSTN2 p.Ile306Asn Likely benign ★★ ⚠ same type
CLSTN2 p.Ala131Thr Uncertain significance ★ ⚠ same type
CLSTN2 p.Ala137Asp Uncertain significance ★ ⚠ same type
CLSTN2 p.Ala243Thr Uncertain significance ★ ⚠ same type
CLSTN2 p.Ala326Asp 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/clstn2-p-gln433arg (accessed [today's date]).

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