Is CREB3L3 p.Pro445Ser (c.1333C>T) pathogenic?

CREB3L3 p.Pro445Ser (c.1333C>T) is classified Uncertain significance in CREB3L3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-26). AlphaMissense: likely benign (0.0707); Very rare (popmax 8.48e-05%, nfe).

How common is CREB3L3 p.Pro445Ser (c.1333C>T) in the general population?

CREB3L3 p.Pro445Ser (c.1333C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CREB3L3 p.Pro445Ser (c.1333C>T)?

AlphaMissense predicts likely benign (score 0.0707) — an in-silico prediction, not a clinical call.

CREB3L3 p.Pro445Ser

c.1333C>T · rs2145146624 · VCV1521621

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0707 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0707	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -5.28	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 0.71	GERP -2.3, phastCons 0.071
Regional constraint	o/e 0.97	unconstrained · MANE · 18 kb · p 0.47 · regional, not allelic
Overall
CADD	1.792	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 8.48e-05% European (non-Finnish) · 1/1,179,464 alleles

Overall 6.2e-05% 1/1,611,750 alleles · very rare exomes 1/1,459,410 · genomes 0/152,340 · joint denominator

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: CREB3L3
Protein: p.Pro445Ser
Coding: c.1333C>T
MANE Select: NM_032607
dbSNP: rs2145146624
Type: single nucleotide variant
Location: chr19:4171916 (GRCh38)
Gene constraint: LOEUF 1.155 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.26
Residue 445: the 'disordered' region; a UniProt-annotated variant site (in hytg2; risk factor; loss of transactivation activity in apoa4, apoc2 or fgf21 promoter-driven luciferase assays)

Full CREB3L3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CREB3L3 p.Pro445Gln Uncertain significance ★ ⚠ same residue
CREB3L3 p.Pro445Leu Uncertain significance ★ ⚠ same residue
CREB3L3 p.Pro445= Likely benign ★ same residue
CREB3L3 p.Arg175Ter Pathogenic/Likely pathogenic ★★ same type
CREB3L3 p.Arg204Ter Pathogenic/Likely pathogenic ★★ same type
CREB3L3 p.Arg242Ter Pathogenic/Likely pathogenic ★★ same type
CREB3L3 p.Trp46Ter Pathogenic/Likely pathogenic ★★ same type
CREB3L3 c.457+5G>A 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/creb3l3-p-pro445ser (accessed [today's date]).

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