Is CREBBP p.Met2115Val (c.6343A>G) pathogenic?

CREBBP p.Met2115Val (c.6343A>G) is classified Conflicting classifications of pathogenicity in CREBBP (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2023-11-18). AlphaMissense: likely benign (0.0807); Ultra-rare (popmax 0.0103%, nfe); Associated with Rubinstein-Taybi syndrome.

What condition is associated with CREBBP p.Met2115Val (c.6343A>G)?

CREBBP p.Met2115Val (c.6343A>G) is associated with Rubinstein-Taybi syndrome (ClinVar).

How common is CREBBP p.Met2115Val (c.6343A>G) in the general population?

CREBBP p.Met2115Val (c.6343A>G) is ultra-rare (popmax 0.0103%, nfe) (gnomAD).

What do computational predictors say about CREBBP p.Met2115Val (c.6343A>G)?

AlphaMissense predicts likely benign (score 0.0807) — an in-silico prediction, not a clinical call.

CREBBP p.Met2115Val

c.6343A>G · rs150774470 · VCV2044338

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0807 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Rubinstein-Taybi syndrome

Computational evidence

Protein change
AlphaMissense	0.0807	likely benign
REVEL	0.2	benign-leaning
SaProt	LLR -7.97	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 1.4	GERP -2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 1,016 bp · p 0.52 · regional, not allelic
Overall
CADD	14.99	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 0.0103% European (non-Finnish) · 121/1,179,992 alleles

Filtering AF 0.00876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0082%

Overall 0.00762% 123/1,613,854 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0103%	9,752
African / African-American	0.00267%	37,462

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.Met2115Val
Coding: c.6343A>G
MANE Select: NM_004380
dbSNP: rs150774470
Type: single nucleotide variant
Location: chr16:3728704 (GRCh38)
Gene constraint: LOEUF 0.101 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.31 · 144 PDB
Residue 2115: 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 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
CREBBP p.Arg1498Ter Pathogenic ★★ same condition
CREBBP p.Arg1867Gln 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-met2115val (accessed [today's date]).

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