Is CREBBP p.Pro1946= (c.5838A>C) pathogenic?

CREBBP p.Pro1946= (c.5838A>C) is classified Benign/Likely benign in CREBBP (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-30). Low-frequency (popmax 2.28%, amr); Associated with Rubinstein-Taybi syndrome.

What condition is associated with CREBBP p.Pro1946= (c.5838A>C)?

CREBBP p.Pro1946= (c.5838A>C) is associated with Rubinstein-Taybi syndrome (ClinVar).

How common is CREBBP p.Pro1946= (c.5838A>C) in the general population?

CREBBP p.Pro1946= (c.5838A>C) is low-frequency (popmax 2.28%, amr) (gnomAD).

CREBBP p.Pro1946=

c.5838A>C · rs1461048336 · VCV1297388

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.28%, amr)

Conditions

Rubinstein-Taybi syndrome

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 -15	GERP -3.5
Overall
CADD	0.173	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.28% Admixed American · 292/12,816 alleles

Filtering AF 2.06% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.98%

Overall 1.8% 4,396/243,854 alleles · low-frequency

Ancestry group	Frequency	1 in
Admixed Americangrpmax	2.28%	44
European (non-Finnish)	1.94%	52
Remaining individualsnot grpmax-eligible	1.71%	58
East Asian	1.62%	62
Ashkenazi Jewishnot grpmax-eligible	1.49%	67
Middle Eastern	1.42%	70
South Asian	1.41%	71
Finnishnot grpmax-eligible	1.39%	72
African / African-American	1.24%	81
Amishnot grpmax-eligible	1.15%	87

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.Pro1946=
Coding: c.5838A>C
MANE Select: NM_004380
dbSNP: rs1461048336
Type: single nucleotide variant
Location: chr16:3729209 (GRCh38)
Gene constraint: LOEUF 0.101 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.31 · 144 PDB
Residue 1946: the 'disordered' region

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

Disease context

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

Similar variants

CREBBP p.Pro1946Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
CREBBP p.Pro1946Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CREBBP p.Pro1946fs Pathogenic/Likely pathogenic ★★ same residue
CREBBP p.Pro1946Ser Uncertain significance ★ ⚠ same residue
CREBBP p.Pro1946Leu Uncertain significance ⚠ same residue
CREBBP c.2881-13G>A Pathogenic/Likely pathogenic ★★ same condition
CREBBP c.3779+1G>A Pathogenic ★★ same condition
CREBBP c.3779+1G>T 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-pro1946 (accessed [today's date]).

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