Is CREBBP p.Arg1985Cys (c.5953C>T) pathogenic?

CREBBP p.Arg1985Cys (c.5953C>T) is classified Uncertain significance in CREBBP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-05). AlphaMissense: likely benign (0.2829); Very rare (popmax 0.00226%, sas); Associated with Rubinstein-Taybi syndrome.

What condition is associated with CREBBP p.Arg1985Cys (c.5953C>T)?

CREBBP p.Arg1985Cys (c.5953C>T) is associated with Rubinstein-Taybi syndrome (ClinVar).

How common is CREBBP p.Arg1985Cys (c.5953C>T) in the general population?

CREBBP p.Arg1985Cys (c.5953C>T) is very rare (popmax 0.00226%, sas) (gnomAD).

What do computational predictors say about CREBBP p.Arg1985Cys (c.5953C>T)?

AlphaMissense predicts likely benign (score 0.2829) — an in-silico prediction, not a clinical call.

CREBBP p.Arg1985Cys

c.5953C>T · rs767715745 · VCV2882669

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2829 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00226%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Rubinstein-Taybi syndrome

Computational evidence

Protein change
AlphaMissense	0.2829	likely benign
REVEL	0.612	indeterminate
SaProt	LLR -9.87	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 9.8	GERP 0.96, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 568 bp · p 0.93 · 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 0.00226% South Asian · 2/88,540 alleles

Filtering AF 0.000769% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00061%

Overall 0.00107% 17/1,584,652 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00226%	44,270
European (non-Finnish)	0.00128%	78,081

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.Arg1985Cys
Coding: c.5953C>T
MANE Select: NM_004380
dbSNP: rs767715745
Type: single nucleotide variant
Location: chr16:3729094 (GRCh38)
Gene constraint: LOEUF 0.101 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.31 · 144 PDB
Residue 1985: 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 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
CREBBP p.Arg1233Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition
CREBBP p.Arg1498Ter Pathogenic ★★ same condition
CREBBP p.Arg1867Gln Pathogenic/Likely 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-arg1985cys (accessed [today's date]).

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