Is CREBZF p.Arg186Pro (c.557G>C) pathogenic?

CREBZF p.Arg186Pro (c.557G>C) is classified Uncertain significance in CREBZF (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-27). AlphaMissense: ambiguous (0.5128); Ultra-rare (popmax 0.0173%, afr).

How common is CREBZF p.Arg186Pro (c.557G>C) in the general population?

CREBZF p.Arg186Pro (c.557G>C) is ultra-rare (popmax 0.0173%, afr) (gnomAD).

What do computational predictors say about CREBZF p.Arg186Pro (c.557G>C)?

AlphaMissense predicts ambiguous (score 0.5128) — an in-silico prediction, not a clinical call.

CREBZF p.Arg186Pro

c.557G>C · rs553072253 · VCV2362725

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5128 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5128	ambiguous
REVEL	0.196	benign-leaning
SaProt	LLR -6.35	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 2.5, phastCons 1
Regional constraint	o/e 1.22	unconstrained · MANE · 701 bp · p 7e-05 · regional, not allelic
Overall
CADD	29.6	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 0.0173% African / African-American · 13/74,984 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00812%

Overall 0.00217% 35/1,611,912 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0173%	5,768
Middle Eastern	0.0165%	6,058
Remaining individualsnot grpmax-eligible	0.016%	6,238
South Asian	0.0022%	45,500
Admixed American	0.00167%	59,758
European (non-Finnish)	0.000678%	147,417

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: CREBZF
Protein: p.Arg186Pro
Coding: c.557G>C
MANE Select: NM_001039618
dbSNP: rs553072253
Type: single nucleotide variant
Location: chr11:85664319 (GRCh38)
Gene constraint: LOEUF 0.738 · pLI 0.32 (gnomAD)
Structure: AlphaFold pLDDT 62.65
Residue 186: the 'disordered' region

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

Similar variants

CREBZF p.Ala152Thr Uncertain significance ★ ⚠ same type
CREBZF p.Ala182Thr Uncertain significance ★ ⚠ same type
CREBZF p.Ala269Thr Uncertain significance ★ ⚠ same type
CREBZF p.Ala26Thr Uncertain significance ★ ⚠ same type
CREBZF p.Ala39Val Uncertain significance ★ ⚠ same type
CREBZF p.Ala77Thr Uncertain significance ★ ⚠ same type
CREBZF p.Arg283Gln Uncertain significance ★ ⚠ same type
CREBZF p.Arg346Trp 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/crebzf-p-arg186pro (accessed [today's date]).

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