Is CREB3 p.Arg155Pro (c.464G>C) pathogenic?

CREB3 p.Arg155Pro (c.464G>C) is classified Uncertain significance in CREB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-15). AlphaMissense: likely pathogenic (0.9861); Ultra-rare (popmax 0.069%, sas).

How common is CREB3 p.Arg155Pro (c.464G>C) in the general population?

CREB3 p.Arg155Pro (c.464G>C) is ultra-rare (popmax 0.069%, sas) (gnomAD).

What do computational predictors say about CREB3 p.Arg155Pro (c.464G>C)?

AlphaMissense predicts likely pathogenic (score 0.9861) — an in-silico prediction, not a clinical call.

CREB3 p.Arg155Pro

c.464G>C · VCV4006726

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9861 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.069%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9861	likely pathogenic · top 1% in CREB3
REVEL	0.839	moderately pathogenic-leaning
SaProt	LLR -16.08	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.8	GERP 1.8, phastCons 1
Overall
CADD	28.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.069% South Asian · 61/88,428 alleles

Filtering AF 0.0551% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.05%

Overall 0.00393% 63/1,604,062 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.069%	1,450
Remaining individualsnot grpmax-eligible	0.00322%	31,039

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.Arg155Pro
Coding: c.464G>C
MANE Select: NM_001255978 · reported on NM_006368
Type: single nucleotide variant
Location: chr9:35735137 (GRCh38)
Structure: AlphaFold pLDDT 61.56

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

Similar variants

CREB3 p.Arg155Trp Uncertain significance ★ ⚠ same residue
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.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-arg155pro (accessed [today's date]).

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