Is CDC40 p.Phe502Cys (c.1505T>G) pathogenic?

CDC40 p.Phe502Cys (c.1505T>G) is classified Pathogenic/Likely pathogenic in CDC40 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2021-04-29). AlphaMissense: likely pathogenic (0.9935); Very rare (popmax 0.00134%, afr); Associated with Congenital pontocerebellar hypoplasia.

What condition is associated with CDC40 p.Phe502Cys (c.1505T>G)?

CDC40 p.Phe502Cys (c.1505T>G) is associated with Congenital pontocerebellar hypoplasia, pontocerebellar hypoplasia, type 15 (ClinVar).

How common is CDC40 p.Phe502Cys (c.1505T>G) in the general population?

CDC40 p.Phe502Cys (c.1505T>G) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about CDC40 p.Phe502Cys (c.1505T>G)?

AlphaMissense predicts likely pathogenic (score 0.9935) — an in-silico prediction, not a clinical call.

CDC40 p.Phe502Cys

c.1505T>G · rs779945821 · VCV1065404

Pathogenic/Likely pathogenic No assertion criteria

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9935 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Congenital pontocerebellar hypoplasia

Computational evidence

Protein change
AlphaMissense	0.9935	likely pathogenic ✓ concordant with ClinVar · top 10% in CDC40
REVEL	0.958	strongly pathogenic-leaning
SaProt	LLR -11.83	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 3,918 bp · p 1.7e-05 · regional, not allelic
Overall
CADD	32.0	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 0.00134% African / African-American · 1/74,556 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000435% 7/1,607,692 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,556
European (non-Finnish)	0.000509%	196,338

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: CDC40
Protein: p.Phe502Cys
Coding: c.1505T>G
MANE Select: NM_015891
dbSNP: rs779945821
Type: single nucleotide variant
Location: chr6:110228919 (GRCh38)
Gene constraint: LOEUF 0.491 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 86.76 · 30 PDB
Residue 502: a UniProt-annotated variant site (in pch15; in knockdown cells, unable to rescue higher intron retention levels and to restore normal cell viability, contrary to wild-type; reduced protein levels in homozygous patient's fibroblasts compared to heterozygous or wild-type cells); a β-strand

Full CDC40 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Congenital pontocerebellar hypoplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pontocerebellar hypoplasia, type 15

Similar variants

CDC40 p.Arg322Trp Uncertain significance ★ ⚠ same condition
CDC40 p.Ala33Gly Uncertain significance ★ ⚠ same type
CDC40 p.Ala466Thr Uncertain significance ★ ⚠ same type
CDC40 p.Arg129Lys Uncertain significance ★ ⚠ same type
CDC40 p.Arg323Cys Uncertain significance ★ ⚠ same type
CDC40 p.Asn382His Uncertain significance ★ ⚠ same type
CDC40 p.Asn430Lys Uncertain significance ★ ⚠ same type
CDC40 p.Asn497Thr 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/cdc40-p-phe502cys (accessed [today's date]).

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