Is CREBBP p.Val952Met (c.2854G>A) pathogenic?

CREBBP p.Val952Met (c.2854G>A) is classified Conflicting classifications of pathogenicity in CREBBP (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-12-04). AlphaMissense: likely benign (0.0995); Ultra-rare (popmax 0.0187%, afr); Associated with Rubinstein-Taybi syndrome due to CREBBP mutations.

What condition is associated with CREBBP p.Val952Met (c.2854G>A)?

CREBBP p.Val952Met (c.2854G>A) is associated with Rubinstein-Taybi syndrome due to CREBBP mutations, Rubinstein-Taybi syndrome, Menke-Hennekam syndrome 1 (ClinVar).

How common is CREBBP p.Val952Met (c.2854G>A) in the general population?

CREBBP p.Val952Met (c.2854G>A) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

What do computational predictors say about CREBBP p.Val952Met (c.2854G>A)?

AlphaMissense predicts likely benign (score 0.0995) — an in-silico prediction, not a clinical call.

CREBBP p.Val952Met

c.2854G>A · rs369930675 · VCV998205

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0995 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Rubinstein-Taybi syndrome due to CREBBP mutations

Computational evidence

Protein change
AlphaMissense	0.0995	likely benign
REVEL	0.297	indeterminate
SaProt	LLR -7.99	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 19 kb · p 0.52 · regional, not allelic
Overall
CADD	23.9	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 0.0187% African / African-American · 14/74,902 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.00112% 18/1,613,498 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,350
Admixed American	0.00667%	14,999

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.Val952Met
Coding: c.2854G>A
MANE Select: NM_004380
dbSNP: rs369930675
Type: single nucleotide variant
Location: chr16:3770596 (GRCh38)
Gene constraint: LOEUF 0.101 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.31 · 144 PDB
Residue 952: the 'disordered' region

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: Rubinstein-Taybi syndrome Menke-Hennekam syndrome 1

Similar variants

CREBBP p.Val952Leu 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-val952met (accessed [today's date]).

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