Is CDC45 p.Arg157Cys (c.469C>T) pathogenic?

CDC45 p.Arg157Cys (c.469C>T) is classified Conflicting classifications of pathogenicity in CDC45 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-29). AlphaMissense: likely benign (0.1782); Ultra-rare (popmax 0.0121%, amr); Associated with Meier-Gorlin syndrome 7.

What condition is associated with CDC45 p.Arg157Cys (c.469C>T)?

CDC45 p.Arg157Cys (c.469C>T) is associated with Meier-Gorlin syndrome 7 (ClinVar).

How common is CDC45 p.Arg157Cys (c.469C>T) in the general population?

CDC45 p.Arg157Cys (c.469C>T) is ultra-rare (popmax 0.0121%, amr) (gnomAD).

What do computational predictors say about CDC45 p.Arg157Cys (c.469C>T)?

AlphaMissense predicts likely benign (score 0.1782) — an in-silico prediction, not a clinical call.

CDC45 p.Arg157Cys

c.469C>T · rs540217942 · VCV253100

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1782 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Meier-Gorlin syndrome 7

Computational evidence

Protein change
AlphaMissense	0.1782	likely benign
REVEL	0.336	indeterminate
SaProt	LLR -11.89	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 39 kb · p 0.0069 · regional, not allelic
Overall
CADD	28.1	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 0.0121% Admixed American · 7/57,822 alleles

Filtering AF 0.00605% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00558%

Overall 0.00653% 105/1,608,266 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0121%	8,260
African / African-American	0.00805%	12,424
Remaining individualsnot grpmax-eligible	0.00803%	12,453
European (non-Finnish)	0.0073%	13,707
South Asian	0.00111%	89,736

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.Arg157Cys
Coding: c.469C>T
MANE Select: NM_003504
dbSNP: rs540217942
Type: single nucleotide variant
Location: chr22:19483988 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.59 · 7 PDB
Residue 157: the 'disordered' region; a UniProt-annotated variant site (in mgors7; decreased protein level)

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.Arg157His 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
CDC45 p.Gln68Arg 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-arg157cys (accessed [today's date]).

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