Is CREBBP p.Ala1666Pro (c.4996G>C) pathogenic?

CREBBP p.Ala1666Pro (c.4996G>C) is classified Uncertain significance in CREBBP (ClinVar, Single submitter, 1 submitter; last evaluated 2019-09-24). AlphaMissense: likely pathogenic (0.996); Absent from gnomAD v4.1.

How common is CREBBP p.Ala1666Pro (c.4996G>C) in the general population?

CREBBP p.Ala1666Pro (c.4996G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CREBBP p.Ala1666Pro (c.4996G>C)?

AlphaMissense predicts likely pathogenic (score 0.996) — an in-silico prediction, not a clinical call.

CREBBP p.Ala1666Pro

c.4996G>C · rs1159046430 · VCV1308725

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.996	likely pathogenic
REVEL	0.848	moderately pathogenic-leaning
SaProt	LLR -9.54	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.86, phastCons 1
Regional constraint	o/e 0.40	unconstrained · MANE · 1,647 bp · p 4.8e-14 · regional, not allelic
Overall
CADD	24.9	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

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.Ala1666Pro
Coding: c.4996G>C
MANE Select: NM_004380
dbSNP: rs1159046430
Type: single nucleotide variant
Location: chr16:3731368 (GRCh38)
Gene constraint: LOEUF 0.101 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.31 · 144 PDB
Residue 1666: the 'interaction with trerf1' region; the cbp/p300-type hat domain

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

Similar variants

CREBBP p.Ala1666Gly Uncertain significance ★ ⚠ same residue
CREBBP p.Ala1666Thr Uncertain significance ★ ⚠ same residue
CREBBP c.1823+5G>A Pathogenic/Likely pathogenic ★★ same type
CREBBP c.2881-13G>A Pathogenic/Likely pathogenic ★★ same type
CREBBP c.3369+1G>T Pathogenic/Likely pathogenic ★★ same type
CREBBP c.3779+1G>A Pathogenic ★★ same type
CREBBP c.3779+1G>T Pathogenic ★★ same type
CREBBP c.3836+1G>A Pathogenic ★★ same type

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-ala1666pro (accessed [today's date]).

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