Is CREBBP p.Pro153Leu (c.458C>T) pathogenic?

CREBBP p.Pro153Leu (c.458C>T) is classified Benign/Likely benign in CREBBP (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.1114); Ultra-rare (popmax 0.0584%, nfe); Associated with Rubinstein-Taybi syndrome.

What condition is associated with CREBBP p.Pro153Leu (c.458C>T)?

CREBBP p.Pro153Leu (c.458C>T) is associated with Rubinstein-Taybi syndrome (ClinVar).

How common is CREBBP p.Pro153Leu (c.458C>T) in the general population?

CREBBP p.Pro153Leu (c.458C>T) is ultra-rare (popmax 0.0584%, nfe) (gnomAD).

What do computational predictors say about CREBBP p.Pro153Leu (c.458C>T)?

AlphaMissense predicts likely benign (score 0.1114) — an in-silico prediction, not a clinical call.

CREBBP p.Pro153Leu

c.458C>T · rs146538907 · VCV382751

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1114 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0584%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Rubinstein-Taybi syndrome

Computational evidence

Protein change
AlphaMissense	0.1114	likely benign
REVEL	0.243	benign-leaning
SaProt	LLR -5.97	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 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 69 kb · p 0.4 · regional, not allelic
Overall
CADD	24.2	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 0.0584% European (non-Finnish) · 689/1,180,052 alleles

Filtering AF 0.0547% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0533%

Overall 0.0497% 803/1,614,228 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.548%	182
Finnishnot grpmax-eligible	0.0796%	1,256
European (non-Finnish)grpmax	0.0584%	1,713
Remaining individualsnot grpmax-eligible	0.0464%	2,155
Admixed American	0.0183%	5,457
African / African-American	0.016%	6,254
South Asian	0.00549%	18,217
East Asian	0.00223%	44,890

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro153Leu
Coding: c.458C>T
MANE Select: NM_004380
dbSNP: rs146538907
Type: single nucleotide variant
Location: chr16:3850637 (GRCh38)
Gene constraint: LOEUF 0.101 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.31 · 144 PDB
Residue 153: 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.Pro153= Likely benign ★ 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
CREBBP c.3836+1G>A Pathogenic ★★ same condition
CREBBP p.Arg1103Ter Pathogenic ★★ same condition
CREBBP p.Arg1233Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition
CREBBP p.Arg1498Ter 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-pro153leu (accessed [today's date]).

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