Is CREB5 p.Arg152Cys (c.454C>T) pathogenic?

CREB5 p.Arg152Cys (c.454C>T) is classified Uncertain significance in CREB5 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-17). AlphaMissense: likely pathogenic (0.716); Ultra-rare (popmax 0.0217%, amr).

How common is CREB5 p.Arg152Cys (c.454C>T) in the general population?

CREB5 p.Arg152Cys (c.454C>T) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about CREB5 p.Arg152Cys (c.454C>T)?

AlphaMissense predicts likely pathogenic (score 0.716) — an in-silico prediction, not a clinical call.

CREB5 p.Arg152Cys

c.454C>T · rs374897586 · VCV3077334

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.716 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.716	likely pathogenic
REVEL	0.471	indeterminate
SaProt	LLR -6.85	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 396 kb · p 0.013 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0217% Admixed American · 13/59,968 alleles

Filtering AF 0.0128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.00297% 48/1,613,700 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,613
East Asian	0.00669%	14,957
South Asian	0.00659%	15,166
African / African-American	0.00267%	37,449
European (non-Finnish)	0.00195%	51,299
Remaining individualsnot grpmax-eligible	0.0016%	62,478

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.Arg152Cys
Coding: c.454C>T
MANE Select: NM_182898
dbSNP: rs374897586
Type: single nucleotide variant
Location: chr7:28570527 (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.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
CREB5 p.Arg366Leu 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-arg152cys (accessed [today's date]).

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