Is CDC45 p.Pro463Leu (c.1388C>T) pathogenic?

CDC45 p.Pro463Leu (c.1388C>T) is classified Pathogenic/Likely pathogenic in CDC45 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-11). AlphaMissense: likely benign (0.1591); Ultra-rare (popmax 0.0231%, sas); Associated with Meier-Gorlin syndrome 7.

What condition is associated with CDC45 p.Pro463Leu (c.1388C>T)?

CDC45 p.Pro463Leu (c.1388C>T) is associated with Meier-Gorlin syndrome 7 (ClinVar).

How common is CDC45 p.Pro463Leu (c.1388C>T) in the general population?

CDC45 p.Pro463Leu (c.1388C>T) is ultra-rare (popmax 0.0231%, sas) (gnomAD).

What do computational predictors say about CDC45 p.Pro463Leu (c.1388C>T)?

AlphaMissense predicts likely benign (score 0.1591) — an in-silico prediction, not a clinical call.

CDC45 p.Pro463Leu

c.1388C>T · rs751663397 · VCV617938

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1591 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0231%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Meier-Gorlin syndrome 7

Computational evidence

Protein change
AlphaMissense	0.1591	likely benign ⚠ discordant with ClinVar
REVEL	0.536	indeterminate
SaProt	LLR -9.77	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 39 kb · p 0.0069 · regional, not allelic
Overall
CADD	25.0	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 0.0231% South Asian · 21/91,086 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0129%

Overall 0.00322% 52/1,613,966 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0231%	4,337
Remaining individualsnot grpmax-eligible	0.0064%	15,621
East Asian	0.00445%	22,447
African / African-American	0.00401%	24,967
European (non-Finnish)	0.00178%	56,190
Admixed American	0.00167%	59,992

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.Pro463Leu
Coding: c.1388C>T
MANE Select: NM_003504
dbSNP: rs751663397
Type: single nucleotide variant
Location: chr22:19514996 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.59 · 7 PDB
Residue 463: a UniProt-annotated variant site (in mgors7; likely pathogenic); an α-helix

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.Pro463= Likely benign ★ same residue
CDC45 p.Ile509Val Uncertain significance ★★ ⚠ same condition
CDC45 p.Pro496Leu 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

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-pro463leu (accessed [today's date]).

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