Is CREB1 p.Ile91Thr (c.272T>C) pathogenic?

CREB1 p.Ile91Thr (c.272T>C) is classified Uncertain significance in CREB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: likely benign (0.2166); Very rare (popmax 0.00224%, eas).

How common is CREB1 p.Ile91Thr (c.272T>C) in the general population?

CREB1 p.Ile91Thr (c.272T>C) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about CREB1 p.Ile91Thr (c.272T>C)?

AlphaMissense predicts likely benign (score 0.2166) — an in-silico prediction, not a clinical call.

CREB1 p.Ile91Thr

c.272T>C · VCV4233974

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2166 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2166	likely benign
REVEL	0.305	indeterminate
SaProt	LLR -4.08	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 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.44	unconstrained · MANE · 15 kb · p 5.1e-12 · regional, not allelic
Overall
CADD	23.5	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 0.00224% East Asian · 1/44,726 alleles

Overall 0.000137% 2/1,455,756 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,726
European (non-Finnish)	8.5e-05%	1,176,212

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: CREB1
Protein: p.Ile91Thr
Coding: c.272T>C
MANE Select: NM_004379
Type: single nucleotide variant
Location: chr2:207567473 (GRCh38)
Gene constraint: LOEUF 0.189 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.38 · 4 PDB
Residue 91: the kid domain

Full CREB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CREB1 p.Ile91Met Uncertain significance ★ ⚠ same residue
CREB1 p.Ile91Val Uncertain significance ★ ⚠ same residue
CREB1 p.Ala72= Benign ★★ same type
CREB1 p.Thr194= Benign/Likely benign ★★ same type
CREB1 p.Ala148Thr Uncertain significance ★ ⚠ same type
CREB1 p.Ala150Ser Uncertain significance ★ ⚠ same type
CREB1 p.Ala176Glu Uncertain significance ★ ⚠ same type
CREB1 p.Ala259Thr Uncertain significance ★ ⚠ 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/creb1-p-ile91thr (accessed [today's date]).

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