Is CREB3 p.Arg153Cys (c.457C>T) pathogenic?

CREB3 p.Arg153Cys (c.457C>T) is classified Uncertain significance in CREB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely benign (0.3252); Very rare (popmax 0.00447%, eas).

How common is CREB3 p.Arg153Cys (c.457C>T) in the general population?

CREB3 p.Arg153Cys (c.457C>T) is very rare (popmax 0.00447%, eas) (gnomAD).

What do computational predictors say about CREB3 p.Arg153Cys (c.457C>T)?

AlphaMissense predicts likely benign (score 0.3252) — an in-silico prediction, not a clinical call.

CREB3 p.Arg153Cys

c.457C>T · VCV4233983

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3252 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00447%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3252	likely benign
REVEL	0.64	indeterminate
SaProt	LLR -11.27	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -2.1, 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

Grpmax group 0.00447% East Asian · 2/44,790 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00193% 31/1,602,222 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00447%	22,395
African / African-American	0.00406%	24,635
Remaining individualsnot grpmax-eligible	0.00322%	31,023
European (non-Finnish)	0.00204%	49,053

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: CREB3
Protein: p.Arg153Cys
Coding: c.457C>T
MANE Select: NM_001255978 · reported on NM_006368
Type: single nucleotide variant
Location: chr9:35735130 (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.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
CREB3 p.Arg85Trp 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-arg153cys (accessed [today's date]).

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