Is CDC40 p.Arg323Cys (c.967C>T) pathogenic?

CDC40 p.Arg323Cys (c.967C>T) is classified Uncertain significance in CDC40 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-03). AlphaMissense: likely benign (0.2192); Very rare (popmax 0.00401%, afr).

How common is CDC40 p.Arg323Cys (c.967C>T) in the general population?

CDC40 p.Arg323Cys (c.967C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about CDC40 p.Arg323Cys (c.967C>T)?

AlphaMissense predicts likely benign (score 0.2192) — an in-silico prediction, not a clinical call.

CDC40 p.Arg323Cys

c.967C>T · rs773612198 · VCV2268998

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2192 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2192	likely benign
REVEL	0.425	indeterminate
SaProt	LLR -12.08	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 39 kb · p 5.5e-07 · 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 0.00401% African / African-American · 3/74,808 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00124% 20/1,613,016 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,793
African / African-Americangrpmax	0.00401%	24,936
South Asian	0.00329%	30,353
Remaining individualsnot grpmax-eligible	0.0016%	62,448
European (non-Finnish)	0.000933%	107,208

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg323Cys
Coding: c.967C>T
MANE Select: NM_015891
dbSNP: rs773612198
Type: single nucleotide variant
Location: chr6:110215310 (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

Similar variants

CDC40 p.Ala33Gly Uncertain significance ★ ⚠ same type
CDC40 p.Ala466Thr Uncertain significance ★ ⚠ same type
CDC40 p.Arg129Lys Uncertain significance ★ ⚠ same type
CDC40 p.Arg322Trp 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
CDC40 p.Asn97Thr 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-arg323cys (accessed [today's date]).

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