Is CREBBP p.Ala138Ser (c.412G>T) pathogenic?

CREBBP p.Ala138Ser (c.412G>T) is classified Uncertain significance in CREBBP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-03). AlphaMissense: likely benign (0.0747); Very rare (popmax 0.000254%, nfe); Associated with Rubinstein-Taybi syndrome.

What condition is associated with CREBBP p.Ala138Ser (c.412G>T)?

CREBBP p.Ala138Ser (c.412G>T) is associated with Rubinstein-Taybi syndrome (ClinVar).

How common is CREBBP p.Ala138Ser (c.412G>T) in the general population?

CREBBP p.Ala138Ser (c.412G>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CREBBP p.Ala138Ser (c.412G>T)?

AlphaMissense predicts likely benign (score 0.0747) — an in-silico prediction, not a clinical call.

CREBBP p.Ala138Ser

c.412G>T · VCV4802900

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0747 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Rubinstein-Taybi syndrome

Computational evidence

Protein change
AlphaMissense	0.0747	likely benign
REVEL	0.231	benign-leaning
SaProt	LLR -5.99	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 2.2	GERP 2.8, phastCons 0.98
Regional constraint	o/e 1.05	unconstrained · MANE · 69 kb · p 0.4 · regional, not allelic
Overall
CADD	23.4	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

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,056 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,836 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.Ala138Ser
Coding: c.412G>T
MANE Select: NM_004380
Type: single nucleotide variant
Location: chr16:3850683 (GRCh38)
Gene constraint: LOEUF 0.101 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.31 · 144 PDB
Residue 138: 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 p.Ala138= Benign/Likely benign ★★ same residue
CREBBP p.Ala138Thr Benign/Likely benign ★★ same residue
CREBBP p.Ala138Gly Uncertain significance ★ ⚠ same residue
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

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-ala138ser (accessed [today's date]).

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