Is CDKN3 p.Arg193Trp (c.577C>T) pathogenic?

CDKN3 p.Arg193Trp (c.577C>T) is classified Uncertain significance in CDKN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-11). AlphaMissense: ambiguous (0.378); Very rare (popmax 0.00224%, eas).

How common is CDKN3 p.Arg193Trp (c.577C>T) in the general population?

CDKN3 p.Arg193Trp (c.577C>T) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about CDKN3 p.Arg193Trp (c.577C>T)?

AlphaMissense predicts ambiguous (score 0.378) — an in-silico prediction, not a clinical call.

CDKN3 p.Arg193Trp

c.577C>T · VCV3489703

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.378 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Computational evidence

Protein change
AlphaMissense	0.378	ambiguous
REVEL	0.408	indeterminate
SaProt	LLR -14.19	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.43 · evaluated, not missing
Pangolin	Δ0.31	loss · gain 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 7.5	GERP 2.8, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 23 kb · p 0.00012 · regional, not allelic
Overall
CADD	33.0	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 0.00224% East Asian · 1/44,704 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000206% 3/1,455,960 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,704
European (non-Finnish)	0.00017%	587,527

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: CDKN3
Protein: p.Arg193Trp
Coding: c.577C>T
MANE Select: NM_005192
Type: single nucleotide variant
Location: chr14:54420016 (GRCh38)
Gene constraint: LOEUF 1.123 · pLI 0.39 (gnomAD)
Structure: AlphaFold pLDDT 91.18 · 2 PDB
Residue 193: the tyrosine-protein phosphatase domain; an α-helix

Full CDKN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDKN3 p.Ala179Thr Uncertain significance ★ ⚠ same type
CDKN3 p.Asn91Lys Uncertain significance ★ ⚠ same type
CDKN3 p.Gln166His Uncertain significance ★ ⚠ same type
CDKN3 p.Glu124Gly Uncertain significance ★ ⚠ same type
CDKN3 p.Glu125Asp Uncertain significance ★ ⚠ same type
CDKN3 p.Ile29Met Uncertain significance ★ ⚠ same type
CDKN3 p.Ile75Met Uncertain significance ★ ⚠ same type
CDKN3 p.Ile7Met 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/cdkn3-p-arg193trp (accessed [today's date]).

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