Is CREBBP p.Arg370Pro (c.1109G>C) pathogenic?

CREBBP p.Arg370Pro (c.1109G>C) is classified Uncertain significance in CREBBP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-12-13). AlphaMissense: likely pathogenic (0.9981); Very rare (popmax 0.00133%, afr); Associated with Rubinstein-Taybi syndrome.

What condition is associated with CREBBP p.Arg370Pro (c.1109G>C)?

CREBBP p.Arg370Pro (c.1109G>C) is associated with Rubinstein-Taybi syndrome (ClinVar).

How common is CREBBP p.Arg370Pro (c.1109G>C) in the general population?

CREBBP p.Arg370Pro (c.1109G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CREBBP p.Arg370Pro (c.1109G>C)?

AlphaMissense predicts likely pathogenic (score 0.9981) — an in-silico prediction, not a clinical call.

CREBBP p.Arg370Pro

c.1109G>C · rs1179677806 · VCV1426452

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9981 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Rubinstein-Taybi syndrome

Computational evidence

Protein change
AlphaMissense	0.9981	likely pathogenic · top 7% in CREBBP
REVEL	0.8	moderately pathogenic-leaning
SaProt	LLR -9.11	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.5, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 17 kb · p 0.00046 · regional, not allelic
Overall
CADD	26.8	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 0.00133% African / African-American · 1/75,046 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,880 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,046
European (non-Finnish)	0.000169%	590,016

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.Arg370Pro
Coding: c.1109G>C
MANE Select: NM_004380
dbSNP: rs1179677806
Type: single nucleotide variant
Location: chr16:3793493 (GRCh38)
Gene constraint: LOEUF 0.101 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.31 · 144 PDB
Residue 370: the 'interaction with srcap' 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.Arg370Ter Pathogenic ★★ same residue
CREBBP p.Arg370Gly 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
CREBBP c.3836+1G>A Pathogenic ★★ same condition
CREBBP p.Arg1103Ter Pathogenic ★★ same condition
CREBBP p.Arg1233Lys 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-arg370pro (accessed [today's date]).

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