Is CREB5 p.Pro223Leu (c.668C>T) pathogenic?

CREB5 p.Pro223Leu (c.668C>T) is classified Uncertain significance in CREB5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: likely benign (0.1358); Very rare (popmax 0.00134%, afr).

How common is CREB5 p.Pro223Leu (c.668C>T) in the general population?

CREB5 p.Pro223Leu (c.668C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about CREB5 p.Pro223Leu (c.668C>T)?

AlphaMissense predicts likely benign (score 0.1358) — an in-silico prediction, not a clinical call.

CREB5 p.Pro223Leu

c.668C>T · VCV4656542

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1358 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1358	likely benign
REVEL	0.301	indeterminate
SaProt	LLR -7.83	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 396 kb · p 0.013 · regional, not allelic
Overall
CADD	25.1	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 0.00134% African / African-American · 1/74,882 alleles

Overall 0.000657% 1/152,166 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: CREB5
Protein: p.Pro223Leu
Coding: c.668C>T
MANE Select: NM_182898
Type: single nucleotide variant
Location: chr7:28724298 (GRCh38)
Gene constraint: LOEUF 0.421 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 57.95

Full CREB5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CREB5 p.Ala193Thr Uncertain significance ★ ⚠ same type
CREB5 p.Ala221Asp Uncertain significance ★ ⚠ same type
CREB5 p.Arg152Cys Uncertain significance ★ ⚠ same type
CREB5 p.Arg200Gln Uncertain significance ★ ⚠ same type
CREB5 p.Arg265Gln Uncertain significance ★ ⚠ same type
CREB5 p.Arg26Cys Uncertain significance ★ ⚠ same type
CREB5 p.Arg26His Uncertain significance ★ ⚠ same type
CREB5 p.Arg365Cys 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/creb5-p-pro223leu (accessed [today's date]).

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