Is CREBBP p.Ala2226Val (c.6677C>T) pathogenic?

CREBBP p.Ala2226Val (c.6677C>T) is classified Conflicting classifications of pathogenicity in CREBBP (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-06-16). AlphaMissense: likely benign (0.123); Very rare (popmax 0.00802%, afr); Associated with Inborn genetic diseases.

What condition is associated with CREBBP p.Ala2226Val (c.6677C>T)?

CREBBP p.Ala2226Val (c.6677C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CREBBP p.Ala2226Val (c.6677C>T) in the general population?

CREBBP p.Ala2226Val (c.6677C>T) is very rare (popmax 0.00802%, afr) (gnomAD).

What do computational predictors say about CREBBP p.Ala2226Val (c.6677C>T)?

AlphaMissense predicts likely benign (score 0.123) — an in-silico prediction, not a clinical call.

CREBBP p.Ala2226Val

c.6677C>T · rs754601626 · VCV1754821

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.123 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00802%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.123	likely benign
REVEL	0.172	moderately benign-leaning
SaProt	LLR -7.00	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 9.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 1,016 bp · p 0.52 · regional, not allelic
Overall
CADD	23.2	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 0.00802% African / African-American · 6/74,858 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.00124% 20/1,612,616 alleles · very rare exomes 13/1,460,556 · genomes 7/152,060 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00802%	12,476
South Asian	0.0055%	18,196
East Asian	0.00223%	44,836
Admixed American	0.00167%	59,868
Remaining individualsnot grpmax-eligible	0.0016%	62,356
European (non-Finnish)	0.000509%	196,597

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.Ala2226Val
Coding: c.6677C>T
MANE Select: NM_004380
dbSNP: rs754601626
Type: single nucleotide variant
Location: chr16:3728370 (GRCh38)
Gene constraint: LOEUF 0.101 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.31 · 144 PDB
Residue 2226: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CREBBP p.Ala2226= Conflicting classifications of pathogenicity ★ same residue
CREBBP p.Ala2226Gly Likely benign ★ same residue
CREBBP p.Arg1786Cys Pathogenic/Likely pathogenic ★★ same condition
CREBBP p.Ala1510Val Uncertain significance ★★ ⚠ same condition
CREBBP p.Ala15Gly Uncertain significance ★★ ⚠ same condition
CREBBP p.Ala1830Thr Uncertain significance ★★ ⚠ same condition
CREBBP p.Ala2049Pro Uncertain significance ★★ ⚠ same condition
CREBBP p.Ala828Val Uncertain significance ★★ ⚠ 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-ala2226val (accessed [today's date]).

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