Is CDC45 p.Glu163Lys (c.487G>A) pathogenic?

CDC45 p.Glu163Lys (c.487G>A) is classified Uncertain significance in CDC45 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-30). AlphaMissense: likely benign (0.0937); Ultra-rare (popmax 0.0582%, sas).

How common is CDC45 p.Glu163Lys (c.487G>A) in the general population?

CDC45 p.Glu163Lys (c.487G>A) is ultra-rare (popmax 0.0582%, sas) (gnomAD).

What do computational predictors say about CDC45 p.Glu163Lys (c.487G>A)?

AlphaMissense predicts likely benign (score 0.0937) — an in-silico prediction, not a clinical call.

CDC45 p.Glu163Lys

c.487G>A · rs751248371 · VCV1435607

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0937 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0582%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0937	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -7.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.49	acceptor gain · deltas
Pangolin	Δ0.44	gain · loss 0.10 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 39 kb · p 0.0069 · regional, not allelic
Overall
CADD	33.0	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 0.0582% South Asian · 53/90,996 alleles

Filtering AF 0.0457% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0412%

Overall 0.00341% 55/1,612,400 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0582%	1,717
Remaining individualsnot grpmax-eligible	0.00321%	31,169

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.Glu163Lys
Coding: c.487G>A
MANE Select: NM_003504
dbSNP: rs751248371
Type: single nucleotide variant
Location: chr22:19494327 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.59 · 7 PDB
Residue 163: the 'disordered' region

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

Similar variants

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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
CDC45 p.Arg269Trp 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-glu163lys (accessed [today's date]).

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