Is CREB3L2 p.Arg90Gln (c.269G>A) pathogenic?

CREB3L2 p.Arg90Gln (c.269G>A) is classified Uncertain significance in CREB3L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-08). AlphaMissense: likely benign (0.079); Very rare (popmax 0.00536%, afr).

How common is CREB3L2 p.Arg90Gln (c.269G>A) in the general population?

CREB3L2 p.Arg90Gln (c.269G>A) is very rare (popmax 0.00536%, afr) (gnomAD).

What do computational predictors say about CREB3L2 p.Arg90Gln (c.269G>A)?

AlphaMissense predicts likely benign (score 0.079) — an in-silico prediction, not a clinical call.

CREB3L2 p.Arg90Gln

c.269G>A · rs754799812 · VCV3077320

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.079 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00536%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.079	likely benign
REVEL	0.114	moderately benign-leaning
SaProt	LLR -5.73	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 5	GERP 1.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 96 kb · p 0.38 · regional, not allelic
Overall
CADD	23.8	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 0.00536% African / African-American · 4/74,650 alleles

Filtering AF 0.00181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00157%

Overall 0.00231% 37/1,602,008 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00536%	18,662
European (non-Finnish)	0.00256%	39,118
Remaining individualsnot grpmax-eligible	0.00161%	61,992
Finnishnot grpmax-eligible	0.00158%	63,294
South Asian	0.00112%	89,520

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.Arg90Gln
Coding: c.269G>A
MANE Select: NM_194071
dbSNP: rs754799812
Type: single nucleotide variant
Location: chr7:137928200 (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.Arg90Trp Uncertain significance ★ ⚠ 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.Asn304Ser Uncertain significance ★ ⚠ same type
CREB3L2 p.Asn504Lys 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-arg90gln (accessed [today's date]).

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