Is CDC45 p.Pro496Leu (c.1487C>T) pathogenic?

CDC45 p.Pro496Leu (c.1487C>T) is classified Uncertain significance in CDC45 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-05). AlphaMissense: likely benign (0.2253); Very rare (popmax 0.000593%, nfe); Associated with Meier-Gorlin syndrome 7.

What condition is associated with CDC45 p.Pro496Leu (c.1487C>T)?

CDC45 p.Pro496Leu (c.1487C>T) is associated with Meier-Gorlin syndrome 7 (ClinVar).

How common is CDC45 p.Pro496Leu (c.1487C>T) in the general population?

CDC45 p.Pro496Leu (c.1487C>T) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about CDC45 p.Pro496Leu (c.1487C>T)?

AlphaMissense predicts likely benign (score 0.2253) — an in-silico prediction, not a clinical call.

CDC45 p.Pro496Leu

c.1487C>T · rs1376596361 · VCV617940

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2253 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Meier-Gorlin syndrome 7

Computational evidence

Protein change
AlphaMissense	0.2253	likely benign
REVEL	0.436	indeterminate
SaProt	LLR -7.40	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 39 kb · p 0.0069 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000593% European (non-Finnish) · 7/1,179,998 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,930 alleles · very rare

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: CDC45
Protein: p.Pro496Leu
Coding: c.1487C>T
MANE Select: NM_003504
dbSNP: rs1376596361
Type: single nucleotide variant
Location: chr22:19516573 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.59 · 7 PDB
Residue 496: a UniProt-annotated variant site (in mgors7; likely pathogenic); a UniProt-annotated variant site (in mgors7; uncertain significance); a β-strand

Full CDC45 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Meier-Gorlin syndrome 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDC45 p.Pro463Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
CDC45 p.Ile509Val Uncertain significance ★★ ⚠ same condition
CDC45 p.Ala298Val Likely pathogenic ★ ⚠ same condition
CDC45 p.Asn76His Likely pathogenic ★ same condition
CDC45 p.Asp226Gly Likely pathogenic ★ ⚠ same condition
CDC45 p.Gln68Arg Likely pathogenic ★ ⚠ same condition
CDC45 p.Glu548Ter Pathogenic ★ same condition
CDC45 p.Arg157Cys Conflicting classifications of pathogenicity ★ ⚠ same condition

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/cdc45-p-pro496leu (accessed [today's date]).

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