Is CREBBP p.Ala631= (c.1893C>T) pathogenic?

CREBBP p.Ala631= (c.1893C>T) is classified Uncertain significance in CREBBP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-15). Very rare (popmax 0.00167%, amr); Associated with Rubinstein-Taybi syndrome due to CREBBP mutations.

What condition is associated with CREBBP p.Ala631= (c.1893C>T)?

CREBBP p.Ala631= (c.1893C>T) is associated with Rubinstein-Taybi syndrome due to CREBBP mutations, Menke-Hennekam syndrome 1 (ClinVar).

How common is CREBBP p.Ala631= (c.1893C>T) in the general population?

CREBBP p.Ala631= (c.1893C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

CREBBP p.Ala631=

c.1893C>T · VCV3580652

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

Rubinstein-Taybi syndrome due to CREBBP mutations

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.54	GERP -5.7, phastCons 0.99
Overall
CADD	10.12	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,004 alleles

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

Overall 0.000186% 3/1,613,974 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,004
European (non-Finnish)	0.000169%	589,984

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.Ala631=
Coding: c.1893C>T
MANE Select: NM_004380
Type: single nucleotide variant
Location: chr16:3778748 (GRCh38)
Gene constraint: LOEUF 0.101 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.31 · 144 PDB
Residue 631: an α-helix; the kix domain

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

Disease context

Rubinstein-Taybi syndrome due to CREBBP mutations — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Menke-Hennekam syndrome 1

Similar variants

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
CREBBP p.Ala1782Thr 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-ala631 (accessed [today's date]).

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