Is CREBZF p.His330Pro (c.989A>C) pathogenic?

CREBZF p.His330Pro (c.989A>C) is classified Uncertain significance in CREBZF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: likely pathogenic (0.9979); Very rare (popmax 0.00949%, nfe).

How common is CREBZF p.His330Pro (c.989A>C) in the general population?

CREBZF p.His330Pro (c.989A>C) is very rare (popmax 0.00949%, nfe) (gnomAD).

What do computational predictors say about CREBZF p.His330Pro (c.989A>C)?

AlphaMissense predicts likely pathogenic (score 0.9979) — an in-silico prediction, not a clinical call.

CREBZF p.His330Pro

c.989A>C · rs765922496 · VCV3077370

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9979 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00949%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9979	likely pathogenic · top 5% in CREBZF
REVEL	0.558	indeterminate
SaProt	LLR -18.79	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 303 bp · p 0.083 · regional, not allelic
Overall
CADD	29.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00949% European (non-Finnish) · 112/1,179,950 alleles

Filtering AF 0.00804% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00752%

Overall 0.00732% 118/1,612,318 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00949%	10,535
African / African-American	0.00401%	24,934
Admixed American	0.00167%	59,976
Remaining individualsnot grpmax-eligible	0.0016%	62,458
South Asian	0.0011%	91,054

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.His330Pro
Coding: c.989A>C
MANE Select: NM_001039618
dbSNP: rs765922496
Type: single nucleotide variant
Location: chr11:85663887 (GRCh38)
Gene constraint: LOEUF 0.738 · pLI 0.32 (gnomAD)
Structure: AlphaFold pLDDT 62.65

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

Similar variants

CREBZF p.His330Gln Uncertain significance ★ ⚠ same residue
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.Arg186Pro 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-his330pro (accessed [today's date]).

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