Is CREBBP p.Pro2003Ser (c.6007C>T) pathogenic?

CREBBP p.Pro2003Ser (c.6007C>T) is classified Uncertain significance in CREBBP (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-19). AlphaMissense: likely benign (0.099); Very rare (popmax 0.00134%, afr); Associated with Rubinstein-Taybi syndrome due to CREBBP mutations.

What condition is associated with CREBBP p.Pro2003Ser (c.6007C>T)?

CREBBP p.Pro2003Ser (c.6007C>T) is associated with Rubinstein-Taybi syndrome due to CREBBP mutations (ClinVar).

How common is CREBBP p.Pro2003Ser (c.6007C>T) in the general population?

CREBBP p.Pro2003Ser (c.6007C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about CREBBP p.Pro2003Ser (c.6007C>T)?

AlphaMissense predicts likely benign (score 0.099) — an in-silico prediction, not a clinical call.

CREBBP p.Pro2003Ser

c.6007C>T · rs1282498604 · VCV1275744

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.099 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Rubinstein-Taybi syndrome due to CREBBP mutations

Computational evidence

Protein change
AlphaMissense	0.099	likely benign
REVEL	0.276	benign-leaning
SaProt	LLR -7.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP -0.35, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 568 bp · p 0.93 · regional, not allelic
Overall
CADD	22.3	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 0.00134% African / African-American · 1/74,662 alleles

Overall 0.000126% 2/1,587,784 alleles · very rare exomes 2/1,435,528 · genomes 0/152,256 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,662
South Asian	0.00112%	89,176

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.Pro2003Ser
Coding: c.6007C>T
MANE Select: NM_004380
dbSNP: rs1282498604
Type: single nucleotide variant
Location: chr16:3729040 (GRCh38)
Gene constraint: LOEUF 0.101 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.31 · 144 PDB
Residue 2003: 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

Similar variants

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
CREBBP p.Ala1782Val Pathogenic/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/crebbp-p-pro2003ser (accessed [today's date]).

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