Is CREB3 p.Pro40Leu (c.119C>T) pathogenic?

CREB3 p.Pro40Leu (c.119C>T) is classified Uncertain significance in CREB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-22). AlphaMissense: likely benign (0.1115); Ultra-rare (popmax 0.0165%, mid).

How common is CREB3 p.Pro40Leu (c.119C>T) in the general population?

CREB3 p.Pro40Leu (c.119C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CREB3 p.Pro40Leu (c.119C>T)?

AlphaMissense predicts likely benign (score 0.1115) — an in-silico prediction, not a clinical call.

CREB3 p.Pro40Leu

c.119C>T · rs1826116241 · VCV2285143

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1115 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1115	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -7.62	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 0.58	GERP -0.71, phastCons 0.052
Regional constraint	o/e 1.01	unconstrained · MANE · 3,950 bp · p 0.87 · regional, not allelic
Overall
CADD	7.915	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 0.0165% Middle Eastern · 1/6,060 alleles

Overall 0.000124% 2/1,613,804 alleles · ultra-rare exomes 2/1,461,434 · genomes 0/152,370 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
European (non-Finnish)	8.48e-05%	1,179,874

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.Pro40Leu
Coding: c.119C>T
MANE Select: NM_006368
dbSNP: rs1826116241
Type: single nucleotide variant
Location: chr9:35732891 (GRCh38)
Gene constraint: LOEUF 1.145 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.35
Residue 40: the 'transcription activation (acidic)' region

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-pro40leu (accessed [today's date]).

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