Is CREBBP p.Ser23= (c.69G>A) pathogenic?

CREBBP p.Ser23= (c.69G>A) is classified Conflicting classifications of pathogenicity in CREBBP (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-04-15). Very rare (popmax 0.00836%, amr); Associated with Rubinstein-Taybi syndrome due to CREBBP mutations.

What condition is associated with CREBBP p.Ser23= (c.69G>A)?

CREBBP p.Ser23= (c.69G>A) is associated with Rubinstein-Taybi syndrome due to CREBBP mutations, Rubinstein-Taybi syndrome, Menke-Hennekam syndrome 1 (ClinVar).

How common is CREBBP p.Ser23= (c.69G>A) in the general population?

CREBBP p.Ser23= (c.69G>A) is very rare (popmax 0.00836%, amr) (gnomAD).

CREBBP p.Ser23=

c.69G>A · rs766095612 · VCV1048115

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00836%, amr)

Conditions

Rubinstein-Taybi syndrome due to CREBBP mutations

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.56	GERP -1.6, phastCons 0.03
Overall
CADD	11.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00836% Admixed American · 5/59,800 alleles

Filtering AF 0.00324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00149% 24/1,610,858 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00836%	11,960
Remaining individualsnot grpmax-eligible	0.00642%	15,585
Finnishnot grpmax-eligible	0.00314%	31,854
European (non-Finnish)	0.0011%	90,673

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: CREBBP
Protein: p.Ser23=
Coding: c.69G>A
MANE Select: NM_004380
dbSNP: rs766095612
Type: single nucleotide variant
Location: chr16:3879848 (GRCh38)
Gene constraint: LOEUF 0.101 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.31 · 144 PDB
Residue 23: the 'disordered' region

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

Disease context

Rubinstein-Taybi syndrome due to CREBBP mutations — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Rubinstein-Taybi syndrome Menke-Hennekam syndrome 1

Similar variants

CREBBP p.Ser23Pro Uncertain significance ★ ⚠ same residue
CREBBP c.2881-13G>A Pathogenic/Likely pathogenic ★★ same condition
CREBBP c.3369+1G>T Pathogenic/Likely pathogenic ★★ same condition
CREBBP c.3779+1G>A Pathogenic ★★ same condition
CREBBP c.3779+1G>T Pathogenic ★★ same condition
CREBBP c.3836+1G>A Pathogenic ★★ same condition
CREBBP c.3914+3G>T Likely pathogenic ★★ same condition
CREBBP c.3982+1G>A 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/crebbp-p-ser23 (accessed [today's date]).

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