Is CDC45 p.Arg554Gln (c.1661G>A) pathogenic?

CDC45 p.Arg554Gln (c.1661G>A) is classified Uncertain significance in CDC45 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-05). AlphaMissense: likely benign (0.1084); Very rare (popmax 0.00446%, eas).

How common is CDC45 p.Arg554Gln (c.1661G>A) in the general population?

CDC45 p.Arg554Gln (c.1661G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CDC45 p.Arg554Gln (c.1661G>A)?

AlphaMissense predicts likely benign (score 0.1084) — an in-silico prediction, not a clinical call.

CDC45 p.Arg554Gln

c.1661G>A · rs1034546345 · VCV1502628

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1084 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1084	likely benign
REVEL	0.206	benign-leaning
SaProt	LLR -7.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.25	donor loss · deltas
Pangolin	Δ0.29	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 39 kb · p 0.0069 · regional, not allelic
Overall
CADD	32.0	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 0.00446% East Asian · 2/44,888 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.00062% 10/1,613,974 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,444
Admixed American	0.00167%	59,996
Remaining individualsnot grpmax-eligible	0.0016%	62,478
South Asian	0.0011%	91,078
European (non-Finnish)	0.000424%	235,998

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.Arg554Gln
Coding: c.1661G>A
MANE Select: NM_003504
dbSNP: rs1034546345
Type: single nucleotide variant
Location: chr22:19518868 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.59 · 7 PDB
Residue 554: a UniProt-annotated variant site (in mgors7; likely pathogenic); a UniProt-annotated variant site (in mgors7; uncertain significance); an α-helix

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

Similar variants

CDC45 p.Arg554Pro Uncertain significance ★ ⚠ same residue
CDC45 p.Arg554Trp Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg554gln (accessed [today's date]).

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