Is CSN3 p.Pro16Ala (c.46C>G) pathogenic?

CSN3 p.Pro16Ala (c.46C>G) is classified Uncertain significance in CSN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-07). AlphaMissense: likely benign (0.2618); Absent from gnomAD v4.1.

How common is CSN3 p.Pro16Ala (c.46C>G) in the general population?

CSN3 p.Pro16Ala (c.46C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CSN3 p.Pro16Ala (c.46C>G)?

AlphaMissense predicts likely benign (score 0.2618) — an in-silico prediction, not a clinical call.

CSN3 p.Pro16Ala

c.46C>G · VCV4657199

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2618 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,564,576)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2618	likely benign
REVEL	0.143	moderately benign-leaning
SaProt	LLR -9.86	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 1.3	GERP 0.91, phastCons 1
Overall
CADD	19.15	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

No allele count reported in gnomAD v4.1 (AN 1,564,576). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CSN3
Protein: p.Pro16Ala
Coding: c.46C>G
MANE Select: NM_003653 · reported on NM_001394997
Type: single nucleotide variant
Location: chr4:70244865 (GRCh38)
Structure: AlphaFold pLDDT 84.64 · 28 PDB

Full CSN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COPS3 p.Ala371Gly Uncertain significance ★ ⚠ same type
COPS3 p.Arg119Gln Uncertain significance ★ ⚠ same type
COPS3 p.Asn109Ile Uncertain significance ★ ⚠ same type
COPS3 p.Gln308Arg Uncertain significance ★ ⚠ same type
COPS3 p.Gln82His Uncertain significance ★ ⚠ same type
COPS3 p.Glu75Lys Uncertain significance ★ ⚠ same type
COPS3 p.Ile228Thr Uncertain significance ★ ⚠ same type
COPS3 p.Ile351Val 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/csn3-p-pro16ala (accessed [today's date]).

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