Is CREBBP p.Pro84Arg (c.251C>G) pathogenic?

CREBBP p.Pro84Arg (c.251C>G) is classified Uncertain significance in CREBBP (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-10-19). AlphaMissense: likely benign (0.2155); Very rare (popmax 8.47e-05%, nfe); Associated with CREBBP-related disorder.

What condition is associated with CREBBP p.Pro84Arg (c.251C>G)?

CREBBP p.Pro84Arg (c.251C>G) is associated with CREBBP-related disorder (ClinVar).

How common is CREBBP p.Pro84Arg (c.251C>G) in the general population?

CREBBP p.Pro84Arg (c.251C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CREBBP p.Pro84Arg (c.251C>G)?

AlphaMissense predicts likely benign (score 0.2155) — an in-silico prediction, not a clinical call.

CREBBP p.Pro84Arg

c.251C>G · VCV3356984

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2155 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

CREBBP-related disorder

Computational evidence

Protein change
AlphaMissense	0.2155	likely benign
REVEL	0.399	indeterminate
SaProt	LLR -8.38	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 69 kb · p 0.4 · regional, not allelic
Overall
CADD	24.8	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 8.47e-05% European (non-Finnish) · 1/1,180,048 alleles

Overall 6.2e-05% 1/1,614,008 alleles · very rare exomes 0/1,461,858 · genomes 1/152,150 · joint denominator

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.Pro84Arg
Coding: c.251C>G
MANE Select: NM_004380
Type: single nucleotide variant
Location: chr16:3850844 (GRCh38)
Gene constraint: LOEUF 0.101 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.31 · 144 PDB
Residue 84: the 'disordered' region

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

Disease context

CREBBP-related disorder

Similar variants

CREBBP p.Pro84Ala Uncertain significance ⚠ same residue
CREBBP p.Pro84Thr Benign/Likely benign ★★ same residue
CREBBP p.Pro84= Conflicting classifications of pathogenicity ★ same residue
CREBBP p.Pro84Ser Uncertain significance ★ ⚠ same residue
CREBBP c.1823+5G>A Pathogenic/Likely pathogenic ★★ same condition
CREBBP c.3779+1G>T Pathogenic ★★ same condition
CREBBP p.Arg1378Pro Pathogenic/Likely pathogenic ★★ ⚠ same condition
CREBBP p.Arg1392Ter 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-pro84arg (accessed [today's date]).

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