Is CDC45 p.Asn540Asp (c.1618A>G) pathogenic?

CDC45 p.Asn540Asp (c.1618A>G) is classified Likely benign in CDC45 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-10-03). AlphaMissense: likely benign (0.0723); Rare (popmax 0.158%, eas); Associated with microcephaly.

What condition is associated with CDC45 p.Asn540Asp (c.1618A>G)?

CDC45 p.Asn540Asp (c.1618A>G) is associated with microcephaly (ClinVar).

How common is CDC45 p.Asn540Asp (c.1618A>G) in the general population?

CDC45 p.Asn540Asp (c.1618A>G) is rare (popmax 0.158%, eas) (gnomAD).

What do computational predictors say about CDC45 p.Asn540Asp (c.1618A>G)?

AlphaMissense predicts likely benign (score 0.0723) — an in-silico prediction, not a clinical call.

CDC45 p.Asn540Asp

c.1618A>G · rs200986651 · VCV813622

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0723 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.158%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microcephaly

Computational evidence

Protein change
AlphaMissense	0.0723	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -2.60	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 39 kb · p 0.0069 · regional, not allelic
Overall
CADD	19.98	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 0.158% East Asian · 71/44,870 alleles

Filtering AF 0.129% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.118%

Overall 0.00477% 77/1,613,996 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.158%	632
Remaining individualsnot grpmax-eligible	0.0048%	20,832
South Asian	0.00329%	30,359

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.Asn540Asp
Coding: c.1618A>G
MANE Select: NM_003504
dbSNP: rs200986651
Type: single nucleotide variant
Location: chr22:19516875 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.59 · 7 PDB
Residue 540: a UniProt-annotated variant site (in mgors7; likely pathogenic)

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

Disease context

microcephaly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDC45 p.Asn540= Likely benign ★ same residue
CDC45 p.Pro463Leu Pathogenic/Likely pathogenic ★★ ⚠ same type
CDC45 c.653+4C>T Uncertain significance ★★ same type
CDC45 p.Ala373Val Uncertain significance ★★ ⚠ same type
CDC45 p.Ala38Asp Uncertain significance ★★ ⚠ same type
CDC45 p.Arg157His Uncertain significance ★★ ⚠ same type
CDC45 p.Arg175Gln Uncertain significance ★★ ⚠ same type
CDC45 p.Arg251His 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/cdc45-p-asn540asp (accessed [today's date]).

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