Is CREB1 p.Ala46Gly (c.137C>G) pathogenic?

CREB1 p.Ala46Gly (c.137C>G) is classified Uncertain significance in CREB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-23). AlphaMissense: likely benign (0.0765); Very rare (popmax 0.00221%, nfe).

How common is CREB1 p.Ala46Gly (c.137C>G) in the general population?

CREB1 p.Ala46Gly (c.137C>G) is very rare (popmax 0.00221%, nfe) (gnomAD).

What do computational predictors say about CREB1 p.Ala46Gly (c.137C>G)?

AlphaMissense predicts likely benign (score 0.0765) — an in-silico prediction, not a clinical call.

CREB1 p.Ala46Gly

c.137C>G · rs143117860 · VCV2550269

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0765 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00221%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0765	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -7.71	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 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 4,617 bp · p 0.59 · regional, not allelic
Overall
CADD	22.2	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 0.00221% European (non-Finnish) · 26/1,178,224 alleles

Filtering AF 0.00154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00178% 26/1,459,306 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: CREB1
Protein: p.Ala46Gly
Coding: c.137C>G
MANE Select: NM_004379
dbSNP: rs143117860
Type: single nucleotide variant
Location: chr2:207560248 (GRCh38)
Gene constraint: LOEUF 0.189 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.38 · 4 PDB

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

Similar variants

CREB1 p.Ala46Val 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
CREB1 p.Ala43Glu 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-ala46gly (accessed [today's date]).

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