Is CDC40 p.His549Pro (c.1646A>C) pathogenic?

CDC40 p.His549Pro (c.1646A>C) is classified Uncertain significance in CDC40 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-16). AlphaMissense: likely pathogenic (0.9801); Rare (popmax 0.164%, nfe).

How common is CDC40 p.His549Pro (c.1646A>C) in the general population?

CDC40 p.His549Pro (c.1646A>C) is rare (popmax 0.164%, nfe) (gnomAD).

What do computational predictors say about CDC40 p.His549Pro (c.1646A>C)?

AlphaMissense predicts likely pathogenic (score 0.9801) — an in-silico prediction, not a clinical call.

CDC40 p.His549Pro

c.1646A>C · rs2534472656 · VCV2322031

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9801 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.164%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9801	likely pathogenic
REVEL	0.914	moderately pathogenic-leaning
SaProt	LLR -15.80	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 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	29.0	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 0.164% European (non-Finnish) · 1,899/1,161,126 alleles

Filtering AF 0.157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.155%

Overall 0.132% 2,103/1,592,838 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.164%	611
Middle Eastern	0.15%	669
Remaining individualsnot grpmax-eligible	0.122%	823
Ashkenazi Jewishnot grpmax-eligible	0.0578%	1,731
African / African-American	0.0523%	1,910
South Asian	0.0496%	2,014
East Asian	0.0246%	4,060
Admixed American	0.00667%	14,983
Finnishnot grpmax-eligible	0.00626%	15,973

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.His549Pro
Coding: c.1646A>C
MANE Select: NM_015891
dbSNP: rs2534472656
Type: single nucleotide variant
Location: chr6:110230037 (GRCh38)
Gene constraint: LOEUF 0.491 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 86.76 · 30 PDB
Residue 549: a β-strand

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-his549pro (accessed [today's date]).

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