Is CREB3 p.Glu166Ala (c.497A>C) pathogenic?

CREB3 p.Glu166Ala (c.497A>C) is classified Uncertain significance in CREB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-04). AlphaMissense: ambiguous (0.4299); Absent from gnomAD v4.1.

How common is CREB3 p.Glu166Ala (c.497A>C) in the general population?

CREB3 p.Glu166Ala (c.497A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CREB3 p.Glu166Ala (c.497A>C)?

AlphaMissense predicts ambiguous (score 0.4299) — an in-silico prediction, not a clinical call.

CREB3 p.Glu166Ala

c.497A>C · rs2490806670 · VCV3077306

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4299 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.4299	ambiguous
REVEL	0.45	indeterminate
SaProt	LLR -11.99	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.94 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Overall
CADD	27.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CREB3
Protein: p.Glu166Ala
Coding: c.497A>C
MANE Select: NM_001255978 · reported on NM_006368
dbSNP: rs2490806670
Type: single nucleotide variant
Location: chr9:35735170 (GRCh38)
Structure: AlphaFold pLDDT 61.56

Full CREB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CREB3 c.697-5T>C Benign ★★ same type
CREB3 p.Asn222= Benign ★★ same type
CREB3 p.Ala113Val Uncertain significance ★ ⚠ same type
CREB3 p.Arg153Cys Uncertain significance ★ ⚠ same type
CREB3 p.Arg155Pro Uncertain significance ★ ⚠ same type
CREB3 p.Arg155Trp Uncertain significance ★ ⚠ same type
CREB3 p.Arg168Cys Uncertain significance ★ ⚠ same type
CREB3 p.Arg264Cys 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/creb3-p-glu166ala (accessed [today's date]).

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