Is CREBBP p.Leu59Phe (c.175C>T) pathogenic?

CREBBP p.Leu59Phe (c.175C>T) is classified Conflicting classifications of pathogenicity in CREBBP (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-07-22). AlphaMissense: likely benign (0.099); Very rare (popmax 8.47e-05%, nfe); Associated with Rubinstein-Taybi syndrome.

What condition is associated with CREBBP p.Leu59Phe (c.175C>T)?

CREBBP p.Leu59Phe (c.175C>T) is associated with Rubinstein-Taybi syndrome, Rubinstein-Taybi syndrome due to CREBBP mutations, Menke-Hennekam syndrome 1 (ClinVar).

How common is CREBBP p.Leu59Phe (c.175C>T) in the general population?

CREBBP p.Leu59Phe (c.175C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CREBBP p.Leu59Phe (c.175C>T)?

AlphaMissense predicts likely benign (score 0.099) — an in-silico prediction, not a clinical call.

CREBBP p.Leu59Phe

c.175C>T · rs747862621 · VCV2160354

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.099 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Rubinstein-Taybi syndrome

Computational evidence

Protein change
AlphaMissense	0.099	likely benign
REVEL	0.493	indeterminate
SaProt	LLR -7.68	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 69 kb · p 0.4 · regional, not allelic
Overall
CADD	25.6	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 8.47e-05% European (non-Finnish) · 1/1,180,042 alleles

Overall 0.000657% 1/152,192 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.Leu59Phe
Coding: c.175C>T
MANE Select: NM_004380
dbSNP: rs747862621
Type: single nucleotide variant
Location: chr16:3850920 (GRCh38)
Gene constraint: LOEUF 0.101 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.31 · 144 PDB

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

Also linked: Rubinstein-Taybi syndrome due to CREBBP mutations Menke-Hennekam syndrome 1

Similar variants

CREBBP p.Leu59= Benign/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
CREBBP c.3982+1G>A 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-leu59phe (accessed [today's date]).

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