Is CREBBP p.Ser1078Pro (c.3232T>C) pathogenic?

CREBBP p.Ser1078Pro (c.3232T>C) is classified Benign/Likely benign in CREBBP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-10). AlphaMissense: likely benign (0.1286); Ultra-rare (popmax 0.0165%, sas); Associated with Rubinstein-Taybi syndrome.

What condition is associated with CREBBP p.Ser1078Pro (c.3232T>C)?

CREBBP p.Ser1078Pro (c.3232T>C) is associated with Rubinstein-Taybi syndrome (ClinVar).

How common is CREBBP p.Ser1078Pro (c.3232T>C) in the general population?

CREBBP p.Ser1078Pro (c.3232T>C) is ultra-rare (popmax 0.0165%, sas) (gnomAD).

What do computational predictors say about CREBBP p.Ser1078Pro (c.3232T>C)?

AlphaMissense predicts likely benign (score 0.1286) — an in-silico prediction, not a clinical call.

CREBBP p.Ser1078Pro

c.3232T>C · rs749028913 · VCV2636768

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1286 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Rubinstein-Taybi syndrome

Computational evidence

Protein change
AlphaMissense	0.1286	likely benign
REVEL	0.146	moderately benign-leaning
SaProt	LLR -7.04	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 11	GERP 0.76, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 19 kb · p 0.52 · regional, not allelic
Overall
CADD	22.1	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 0.0165% South Asian · 15/91,092 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00811%

Overall 0.00155% 25/1,614,128 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0165%	6,073
Remaining individualsnot grpmax-eligible	0.0064%	15,622
European (non-Finnish)	0.000508%	196,675

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.Ser1078Pro
Coding: c.3232T>C
MANE Select: NM_004380
dbSNP: rs749028913
Type: single nucleotide variant
Location: chr16:3767738 (GRCh38)
Gene constraint: LOEUF 0.101 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.31 · 144 PDB
Residue 1078: 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.Ser1078= Likely benign ★★ same residue
CREBBP p.Ser1078Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CREBBP p.Ser1078Trp 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

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-ser1078pro (accessed [today's date]).

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