Is CDC34 p.Pro197Leu (c.590C>T) pathogenic?

CDC34 p.Pro197Leu (c.590C>T) is classified Uncertain significance in CDC34 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-20). AlphaMissense: likely benign (0.0713); Very rare (popmax 0.004%, afr).

How common is CDC34 p.Pro197Leu (c.590C>T) in the general population?

CDC34 p.Pro197Leu (c.590C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about CDC34 p.Pro197Leu (c.590C>T)?

AlphaMissense predicts likely benign (score 0.0713) — an in-silico prediction, not a clinical call.

CDC34 p.Pro197Leu

c.590C>T · VCV3998496

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0713 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0713	likely benign
REVEL	0.276	benign-leaning
SaProt	LLR -8.84	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 7.4	GERP 1.1, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,617 bp · p 0.0029 · regional, not allelic
Overall
CADD	21.2	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 0.004% African / African-American · 3/74,920 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00322% 52/1,612,432 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,973
European (non-Finnish)	0.00381%	26,219
South Asian	0.00329%	30,351
Remaining individualsnot grpmax-eligible	0.0016%	62,450

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: CDC34
Protein: p.Pro197Leu
Coding: c.590C>T
MANE Select: NM_004359
Type: single nucleotide variant
Location: chr19:541431 (GRCh38)
Gene constraint: LOEUF 1.136 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.52 · 5 PDB
Residue 197: the 'scf-binding' region

Full CDC34 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDC34 p.Ala176Val Uncertain significance ★ ⚠ same type
CDC34 p.Ala196Val Uncertain significance ★ ⚠ same type
CDC34 p.Ala2Ser Uncertain significance ★ ⚠ same type
CDC34 p.Ala44Val Uncertain significance ★ ⚠ same type
CDC34 p.Arg159Gln Uncertain significance ★ ⚠ same type
CDC34 p.Arg3Gln Uncertain significance ★ ⚠ same type
CDC34 p.Arg61Cys Uncertain significance ★ ⚠ same type
CDC34 p.Arg76Gln 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/cdc34-p-pro197leu (accessed [today's date]).

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