Is CREBBP p.Ala2183Ser (c.6547G>T) pathogenic?

CREBBP p.Ala2183Ser (c.6547G>T) is classified Uncertain significance in CREBBP (ClinVar, Single submitter, 2 submitters; last evaluated 2024-02-14). AlphaMissense: likely benign (0.0753); Absent from gnomAD v4.1; Associated with Menke-Hennekam syndrome 1.

What condition is associated with CREBBP p.Ala2183Ser (c.6547G>T)?

CREBBP p.Ala2183Ser (c.6547G>T) is associated with Menke-Hennekam syndrome 1, Rubinstein-Taybi syndrome due to CREBBP mutations (ClinVar).

How common is CREBBP p.Ala2183Ser (c.6547G>T) in the general population?

CREBBP p.Ala2183Ser (c.6547G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CREBBP p.Ala2183Ser (c.6547G>T)?

AlphaMissense predicts likely benign (score 0.0753) — an in-silico prediction, not a clinical call.

CREBBP p.Ala2183Ser

c.6547G>T · VCV3356718

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0753 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Menke-Hennekam syndrome 1

Computational evidence

Protein change
AlphaMissense	0.0753	likely benign
REVEL	0.211	benign-leaning
SaProt	LLR -7.72	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 3.3	GERP 1.6, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 1,016 bp · p 0.52 · regional, not allelic
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CREBBP
Protein: p.Ala2183Ser
Coding: c.6547G>T
MANE Select: NM_004380
Type: single nucleotide variant
Location: chr16:3728500 (GRCh38)
Gene constraint: LOEUF 0.101 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.31 · 144 PDB
Residue 2183: the 'disordered' region

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

Disease context

Menke-Hennekam syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Rubinstein-Taybi syndrome due to CREBBP mutations

Similar variants

CREBBP p.Ala2183Val Likely benign ★★ ⚠ same residue
CREBBP p.Ala2183= 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

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-ala2183ser (accessed [today's date]).

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