Is CDC40 p.Arg322Trp (c.964C>T) pathogenic?

CDC40 p.Arg322Trp (c.964C>T) is classified Uncertain significance in CDC40 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-20). AlphaMissense: ambiguous (0.476); Ultra-rare (popmax 0.0461%, sas); Associated with pontocerebellar hypoplasia, type 15.

What condition is associated with CDC40 p.Arg322Trp (c.964C>T)?

CDC40 p.Arg322Trp (c.964C>T) is associated with pontocerebellar hypoplasia, type 15 (ClinVar).

How common is CDC40 p.Arg322Trp (c.964C>T) in the general population?

CDC40 p.Arg322Trp (c.964C>T) is ultra-rare (popmax 0.0461%, sas) (gnomAD).

What do computational predictors say about CDC40 p.Arg322Trp (c.964C>T)?

AlphaMissense predicts ambiguous (score 0.476) — an in-silico prediction, not a clinical call.

CDC40 p.Arg322Trp

c.964C>T · VCV3341454

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.476 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0461%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

pontocerebellar hypoplasia, type 15

Computational evidence

Protein change
AlphaMissense	0.476	ambiguous
REVEL	0.805	moderately pathogenic-leaning
SaProt	LLR -14.31	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 0.64, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 39 kb · p 5.5e-07 · regional, not allelic
Overall
CADD	27.5	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 0.0461% South Asian · 42/91,034 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0311%

Overall 0.00322% 52/1,613,170 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0461%	2,167
East Asian	0.00446%	22,431
African / African-American	0.00133%	74,984
European (non-Finnish)	0.000594%	168,463

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.Arg322Trp
Coding: c.964C>T
MANE Select: NM_015891
Type: single nucleotide variant
Location: chr6:110215307 (GRCh38)
Gene constraint: LOEUF 0.491 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 86.76 · 30 PDB

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

Disease context

pontocerebellar hypoplasia, type 15 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDC40 p.Phe502Cys Pathogenic/Likely pathogenic 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-arg322trp (accessed [today's date]).

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