Is CDC37 p.Pro359Leu (c.1076C>T) pathogenic?

CDC37 p.Pro359Leu (c.1076C>T) is classified Uncertain significance in CDC37 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely benign (0.0746); Ultra-rare (popmax 0.035%, amr).

How common is CDC37 p.Pro359Leu (c.1076C>T) in the general population?

CDC37 p.Pro359Leu (c.1076C>T) is ultra-rare (popmax 0.035%, amr) (gnomAD).

What do computational predictors say about CDC37 p.Pro359Leu (c.1076C>T)?

AlphaMissense predicts likely benign (score 0.0746) — an in-silico prediction, not a clinical call.

CDC37 p.Pro359Leu

c.1076C>T · VCV4223253

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0746 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.035%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0746	likely benign
REVEL	0.167	moderately benign-leaning
SaProt	LLR -7.21	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 8.2	GERP 2.1, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 4,648 bp · p 1.6e-05 · regional, not allelic
Overall
CADD	21.5	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 0.035% Admixed American · 21/60,026 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.0013% 21/1,614,204 alleles · ultra-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: CDC37
Protein: p.Pro359Leu
Coding: c.1076C>T
MANE Select: NM_007065
Type: single nucleotide variant
Location: chr19:10391612 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.83 · 19 PDB
Residue 359: the 'disordered' region

Full CDC37 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDC37 p.Phe151= Benign ★★ same type
CDC37 p.Ala329Ser Uncertain significance ★ ⚠ same type
CDC37 p.Ala366Val Uncertain significance ★ ⚠ same type
CDC37 p.Ala86Val Uncertain significance ★ ⚠ same type
CDC37 p.Arg166Cys Uncertain significance ★ ⚠ same type
CDC37 p.Arg235Gln Uncertain significance ★ ⚠ same type
CDC37 p.Arg235Trp Uncertain significance ★ ⚠ same type
CDC37 p.Arg246His 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/cdc37-p-pro359leu (accessed [today's date]).

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