Is CDC45 p.Arg554Trp (c.1660C>T) pathogenic?

CDC45 p.Arg554Trp (c.1660C>T) is classified Conflicting classifications of pathogenicity in CDC45 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2024-06-12). AlphaMissense: likely benign (0.2776); Very rare (popmax 0.00534%, afr); Associated with CDC45-related disorder.

What condition is associated with CDC45 p.Arg554Trp (c.1660C>T)?

CDC45 p.Arg554Trp (c.1660C>T) is associated with CDC45-related disorder, Meier-Gorlin syndrome 7 (ClinVar).

How common is CDC45 p.Arg554Trp (c.1660C>T) in the general population?

CDC45 p.Arg554Trp (c.1660C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about CDC45 p.Arg554Trp (c.1660C>T)?

AlphaMissense predicts likely benign (score 0.2776) — an in-silico prediction, not a clinical call.

CDC45 p.Arg554Trp

c.1660C>T · rs778665661 · VCV253101

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2776 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CDC45-related disorder

Computational evidence

Protein change
AlphaMissense	0.2776	likely benign
REVEL	0.388	indeterminate
SaProt	LLR -10.62	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.45 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 0.41, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 39 kb · p 0.0069 · regional, not allelic
Overall
CADD	26.4	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 0.00534% African / African-American · 4/74,924 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00297% 48/1,613,934 alleles · very rare exomes 41/1,461,778 · genomes 7/152,156 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0473%	2,114
Remaining individualsnot grpmax-eligible	0.0064%	15,621
African / African-Americangrpmax	0.00534%	18,731
European (non-Finnish)	0.00212%	47,198
South Asian	0.0011%	91,066

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg554Trp
Coding: c.1660C>T
MANE Select: NM_003504
dbSNP: rs778665661
Type: single nucleotide variant
Location: chr22:19518867 (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

Disease context

CDC45-related disorder

Also linked: Meier-Gorlin syndrome 7

Similar variants

CDC45 p.Arg554Gln Uncertain significance ★ ⚠ same residue
CDC45 p.Arg554Pro Uncertain significance ★ ⚠ same residue
CDC45 p.Pro463Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
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

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-arg554trp (accessed [today's date]).

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