Is CDC45 p.Ser4Tyr (c.11C>A) pathogenic?

CDC45 p.Ser4Tyr (c.11C>A) is classified Uncertain significance in CDC45 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-23). AlphaMissense: likely benign (0.1228); Very rare (popmax 0.00891%, eas); Associated with Inborn genetic diseases.

What condition is associated with CDC45 p.Ser4Tyr (c.11C>A)?

CDC45 p.Ser4Tyr (c.11C>A) is associated with Inborn genetic diseases (ClinVar).

How common is CDC45 p.Ser4Tyr (c.11C>A) in the general population?

CDC45 p.Ser4Tyr (c.11C>A) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about CDC45 p.Ser4Tyr (c.11C>A)?

AlphaMissense predicts likely benign (score 0.1228) — an in-silico prediction, not a clinical call.

CDC45 p.Ser4Tyr

c.11C>A · VCV4608625

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1228 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1228	likely benign
REVEL	0.158	moderately benign-leaning
SaProt	LLR -9.04	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 2.1	GERP 1.9, phastCons 0.97
Regional constraint	o/e 0.90	unconstrained · MANE · 39 kb · p 0.0069 · regional, not allelic
Overall
CADD	23.8	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 0.00891% East Asian · 4/44,870 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00031% 5/1,613,722 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,218
Admixed American	0.00167%	60,026

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.Ser4Tyr
Coding: c.11C>A
MANE Select: NM_003504
Type: single nucleotide variant
Location: chr22:19479979 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.59 · 7 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDC45 p.Ser4Thr Uncertain significance ★ ⚠ same residue
CDC45 p.Ser4= Likely benign ★ same residue
CDC45 c.653+4C>T Uncertain significance ★★ same condition
CDC45 p.Ala373Val Uncertain significance ★★ ⚠ same condition
CDC45 p.Ala38Asp Uncertain significance ★★ ⚠ same condition
CDC45 p.Arg157His Uncertain significance ★★ ⚠ same condition
CDC45 p.Arg175Gln Uncertain significance ★★ ⚠ same condition
CDC45 p.Arg251His Uncertain significance ★★ ⚠ 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-ser4tyr (accessed [today's date]).

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