Is CSN3 p.Tyr63Phe (c.188A>T) pathogenic?

CSN3 p.Tyr63Phe (c.188A>T) is classified Uncertain significance in CSN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-12). AlphaMissense: likely benign (0.2008); Very rare (popmax 8.48e-05%, nfe).

How common is CSN3 p.Tyr63Phe (c.188A>T) in the general population?

CSN3 p.Tyr63Phe (c.188A>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CSN3 p.Tyr63Phe (c.188A>T)?

AlphaMissense predicts likely benign (score 0.2008) — an in-silico prediction, not a clinical call.

CSN3 p.Tyr63Phe

c.188A>T · rs760344716 · VCV2318654

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2008 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2008	likely benign
REVEL	0.283	benign-leaning
SaProt	LLR -7.52	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 4.5	GERP 1.9, phastCons 1
Overall
CADD	17.77	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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,918 alleles

Overall 6.84e-05% 1/1,461,706 alleles · very rare

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: CSN3
Protein: p.Tyr63Phe
Coding: c.188A>T
MANE Select: NM_003653 · reported on NM_001394997
dbSNP: rs760344716
Type: single nucleotide variant
Location: chr4:70249098 (GRCh38)
Structure: AlphaFold pLDDT 84.64 · 28 PDB

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

Similar variants

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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-tyr63phe (accessed [today's date]).

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