Is CREB3L2 p.Lys356Arg (c.1067A>G) pathogenic?

CREB3L2 p.Lys356Arg (c.1067A>G) is classified Uncertain significance in CREB3L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-20). AlphaMissense: likely benign (0.0929); Very rare (popmax 0.00288%, nfe).

How common is CREB3L2 p.Lys356Arg (c.1067A>G) in the general population?

CREB3L2 p.Lys356Arg (c.1067A>G) is very rare (popmax 0.00288%, nfe) (gnomAD).

What do computational predictors say about CREB3L2 p.Lys356Arg (c.1067A>G)?

AlphaMissense predicts likely benign (score 0.0929) — an in-silico prediction, not a clinical call.

CREB3L2 p.Lys356Arg

c.1067A>G · rs775525222 · VCV3077316

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0929 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00288%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0929	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -5.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.21	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 4.1	GERP 1.8, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 24 kb · p 0.06 · regional, not allelic
Overall
CADD	18.19	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 0.00288% European (non-Finnish) · 34/1,179,968 alleles

Filtering AF 0.00207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00229% 37/1,613,962 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00288%	34,705
South Asian	0.0022%	45,540
African / African-American	0.00133%	74,924

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.Lys356Arg
Coding: c.1067A>G
MANE Select: NM_194071
dbSNP: rs775525222
Type: single nucleotide variant
Location: chr7:137885479 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 55.95
Residue 356: the bzip domain; the 'leucine-zipper' region

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

Similar variants

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
CREB3L2 p.Arg90Trp Uncertain significance ★ ⚠ same type
CREB3L2 p.Asn304Ser 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-lys356arg (accessed [today's date]).

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