Is CREBBP p.Phe1358Ser (c.4073T>C) pathogenic?

CREBBP p.Phe1358Ser (c.4073T>C) is classified Conflicting classifications of pathogenicity in CREBBP (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-15). AlphaMissense: likely benign (0.2709); Very rare (popmax 0.00446%, eas); Associated with CREBBP-related disorder.

What condition is associated with CREBBP p.Phe1358Ser (c.4073T>C)?

CREBBP p.Phe1358Ser (c.4073T>C) is associated with CREBBP-related disorder, Rubinstein-Taybi syndrome (ClinVar).

How common is CREBBP p.Phe1358Ser (c.4073T>C) in the general population?

CREBBP p.Phe1358Ser (c.4073T>C) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CREBBP p.Phe1358Ser (c.4073T>C)?

AlphaMissense predicts likely benign (score 0.2709) — an in-silico prediction, not a clinical call.

CREBBP p.Phe1358Ser

c.4073T>C · rs762638591 · VCV1206706

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2709 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CREBBP-related disorder

Computational evidence

Protein change
AlphaMissense	0.2709	likely benign
REVEL	0.327	indeterminate
SaProt	LLR -4.88	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 7.1	GERP -0.36, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 22 kb · p 4.3e-21 · regional, not allelic
Overall
CADD	25.3	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 0.00446% East Asian · 2/44,888 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.00105% 17/1,614,086 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0208%	4,807
East Asiangrpmax	0.00446%	22,444
Admixed American	0.00333%	30,001

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe1358Ser
Coding: c.4073T>C
MANE Select: NM_004380
dbSNP: rs762638591
Type: single nucleotide variant
Location: chr16:3740459 (GRCh38)
Gene constraint: LOEUF 0.101 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.31 · 144 PDB
Residue 1358: the cbp/p300-type hat domain

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

Disease context

CREBBP-related disorder

Also linked: Rubinstein-Taybi syndrome

Similar variants

CREBBP c.1823+5G>A Pathogenic/Likely pathogenic ★★ same condition
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.Arg1378Pro 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-phe1358ser (accessed [today's date]).

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