Is CREB3 p.Val88Leu (c.262G>C) pathogenic?

CREB3 p.Val88Leu (c.262G>C) is classified Uncertain significance in CREB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-28). AlphaMissense: likely benign (0.1423); Very rare (popmax 0.00223%, eas).

How common is CREB3 p.Val88Leu (c.262G>C) in the general population?

CREB3 p.Val88Leu (c.262G>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CREB3 p.Val88Leu (c.262G>C)?

AlphaMissense predicts likely benign (score 0.1423) — an in-silico prediction, not a clinical call.

CREB3 p.Val88Leu

c.262G>C · VCV3496937

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1423 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1423	likely benign
REVEL	0.149	moderately benign-leaning
SaProt	LLR -5.88	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 1.4	GERP 0.37, phastCons 0.006
Overall
CADD	9.834	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 0.00223% East Asian · 1/44,888 alleles

Overall 0.000137% 2/1,461,890 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,888
European (non-Finnish)	8.47e-05%	1,180,043

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.Val88Leu
Coding: c.262G>C
MANE Select: NM_001255978 · reported on NM_006368
Type: single nucleotide variant
Location: chr9:35733128 (GRCh38)
Structure: AlphaFold pLDDT 61.56
Residue 88: the 'disordered' 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-val88leu (accessed [today's date]).

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