Is CREBBP p.Ser2065Arg (c.6195C>A) pathogenic?

CREBBP p.Ser2065Arg (c.6195C>A) is classified Uncertain significance in CREBBP (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-04-11). AlphaMissense: likely pathogenic (0.819); Very rare (popmax 6.85e-05%); Associated with Inborn genetic diseases.

What condition is associated with CREBBP p.Ser2065Arg (c.6195C>A)?

CREBBP p.Ser2065Arg (c.6195C>A) is associated with Inborn genetic diseases, Rubinstein-Taybi syndrome due to CREBBP mutations, Rubinstein-Taybi syndrome (ClinVar).

How common is CREBBP p.Ser2065Arg (c.6195C>A) in the general population?

CREBBP p.Ser2065Arg (c.6195C>A) is very rare (popmax 6.85e-05%) (gnomAD).

What do computational predictors say about CREBBP p.Ser2065Arg (c.6195C>A)?

AlphaMissense predicts likely pathogenic (score 0.819) — an in-silico prediction, not a clinical call.

CREBBP p.Ser2065Arg

c.6195C>A · rs374150949 · VCV977430

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.819 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.85e-05%)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.819	likely pathogenic
REVEL	0.198	benign-leaning
SaProt	LLR -8.53	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -3.2
Regional constraint	o/e 0.99	unconstrained · MANE · 568 bp · p 0.93 · regional, not allelic
Overall
CADD	14.92	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 6.85e-05%

Overall 6.85e-05% 1/1,460,820 alleles · very rare

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.Ser2065Arg
Coding: c.6195C>A
MANE Select: NM_004380
dbSNP: rs374150949
Type: single nucleotide variant
Location: chr16:3728852 (GRCh38)
Gene constraint: LOEUF 0.101 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.31 · 144 PDB
Residue 2065: a turn

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Rubinstein-Taybi syndrome due to CREBBP mutations Rubinstein-Taybi syndrome Menke-Hennekam syndrome 1

Similar variants

CREBBP p.Ser2065= Benign/Likely benign ★★ same residue
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

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-ser2065arg (accessed [today's date]).

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