Is CREB3L2 p.Pro438Ser (c.1312C>T) pathogenic?

CREB3L2 p.Pro438Ser (c.1312C>T) is classified Uncertain significance in CREB3L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: likely benign (0.0687); Very rare (popmax 0.000424%, nfe).

How common is CREB3L2 p.Pro438Ser (c.1312C>T) in the general population?

CREB3L2 p.Pro438Ser (c.1312C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about CREB3L2 p.Pro438Ser (c.1312C>T)?

AlphaMissense predicts likely benign (score 0.0687) — an in-silico prediction, not a clinical call.

CREB3L2 p.Pro438Ser

c.1312C>T · VCV4233996

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0687 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0687	likely benign
REVEL	0.06	moderately benign-leaning
SaProt	LLR -6.07	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 1.8	GERP -1.1, phastCons 0.97
Regional constraint	o/e 1.12	unconstrained · MANE · 24 kb · p 0.06 · regional, not allelic
Overall
CADD	14.42	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 0.000424% European (non-Finnish) · 5/1,178,348 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000343% 5/1,459,556 alleles · very rare

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: CREB3L2
Protein: p.Pro438Ser
Coding: c.1312C>T
MANE Select: NM_194071
Type: single nucleotide variant
Location: chr7:137882587 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 55.95

Full CREB3L2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CREB3L2 p.Pro438Thr Uncertain significance ★ ⚠ same residue
CREB3L2 p.Pro438Leu Likely benign ★ same residue
CREB3L2 p.Ala294Ser Uncertain significance ★ ⚠ same type
CREB3L2 p.Arg223Cys Uncertain significance ★ ⚠ same type
CREB3L2 p.Arg241Gln Uncertain significance ★ ⚠ same type
CREB3L2 p.Arg299Gln Uncertain significance ★ ⚠ same type
CREB3L2 p.Arg348Ser Uncertain significance ★ ⚠ same type
CREB3L2 p.Arg90Gln 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/creb3l2-p-pro438ser (accessed [today's date]).

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