Is CREBBP p.Arg1378Pro (c.4133G>C) pathogenic?

CREBBP p.Arg1378Pro (c.4133G>C) is classified Pathogenic/Likely pathogenic in CREBBP (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-02-19). AlphaMissense: likely pathogenic (0.9964); Absent from gnomAD v4.1; Associated with CREBBP-related disorder.

What condition is associated with CREBBP p.Arg1378Pro (c.4133G>C)?

CREBBP p.Arg1378Pro (c.4133G>C) is associated with CREBBP-related disorder, Rubinstein-Taybi syndrome due to CREBBP mutations (ClinVar).

How common is CREBBP p.Arg1378Pro (c.4133G>C) in the general population?

CREBBP p.Arg1378Pro (c.4133G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CREBBP p.Arg1378Pro (c.4133G>C)?

AlphaMissense predicts likely pathogenic (score 0.9964) — an in-silico prediction, not a clinical call.

CREBBP p.Arg1378Pro

c.4133G>C · rs121434626 · VCV9430

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9964 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,614,134)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CREBBP-related disorder

Computational evidence

Protein change
AlphaMissense	0.9964	likely pathogenic ✓ concordant with ClinVar
REVEL	0.918	moderately pathogenic-leaning
SaProt	LLR -9.90	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.85	donor loss · deltas
Pangolin	Δ0.82	loss · gain 0.08 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 22 kb · p 4.3e-21 · regional, not allelic
Overall
CADD	34.0	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

No allele count reported in gnomAD v4.1 (AN 1,614,134). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CREBBP
Protein: p.Arg1378Pro
Coding: c.4133G>C
MANE Select: NM_004380
dbSNP: rs121434626
Type: single nucleotide variant
Location: chr16:3740399 (GRCh38)
Gene constraint: LOEUF 0.101 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.31 · 144 PDB
Residue 1378: a UniProt-annotated variant site (in rsts1; abolishes acetyltransferase activity and the ability of transactivate creb); the cbp/p300-type hat domain

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

Disease context

CREBBP-related disorder

Also linked: Rubinstein-Taybi syndrome due to CREBBP mutations

Similar variants

CREBBP p.Arg1378Gln Pathogenic ★★ ⚠ same residue
CREBBP p.Arg1378Trp Uncertain significance ★ ⚠ same residue
CREBBP c.1823+5G>A Pathogenic/Likely pathogenic ★★ same condition
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

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-arg1378pro (accessed [today's date]).

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