Is CDC40 p.Met481Val (c.1441A>G) pathogenic?

CDC40 p.Met481Val (c.1441A>G) is classified Uncertain significance in CDC40 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-16). AlphaMissense: likely pathogenic (0.836); Ultra-rare (popmax 0.0128%, amr).

How common is CDC40 p.Met481Val (c.1441A>G) in the general population?

CDC40 p.Met481Val (c.1441A>G) is ultra-rare (popmax 0.0128%, amr) (gnomAD).

What do computational predictors say about CDC40 p.Met481Val (c.1441A>G)?

AlphaMissense predicts likely pathogenic (score 0.836) — an in-silico prediction, not a clinical call.

CDC40 p.Met481Val

c.1441A>G · rs1004630695 · VCV3140840

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.836 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0128%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.836	likely pathogenic
REVEL	0.582	indeterminate
SaProt	LLR -13.71	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	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	24.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0128% Admixed American · 7/54,774 alleles

Filtering AF 0.00599% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0042%

Overall 0.000627% 10/1,594,482 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0128%	7,825
Remaining individualsnot grpmax-eligible	0.00324%	30,838
European (non-Finnish)	8.51e-05%	1,174,896

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.Met481Val
Coding: c.1441A>G
MANE Select: NM_015891
dbSNP: rs1004630695
Type: single nucleotide variant
Location: chr6:110228855 (GRCh38)
Gene constraint: LOEUF 0.491 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 86.76 · 30 PDB
Residue 481: a turn

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.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-met481val (accessed [today's date]).

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