Is CEBPZ p.Phe220Leu (c.658T>C) pathogenic?

CEBPZ p.Phe220Leu (c.658T>C) is classified Uncertain significance in CEBPZ (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-24). AlphaMissense: likely pathogenic (0.7691); Ultra-rare (popmax 0.0164%, mid).

How common is CEBPZ p.Phe220Leu (c.658T>C) in the general population?

CEBPZ p.Phe220Leu (c.658T>C) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CEBPZ p.Phe220Leu (c.658T>C)?

AlphaMissense predicts likely pathogenic (score 0.7691) — an in-silico prediction, not a clinical call.

CEBPZ p.Phe220Leu

c.658T>C · VCV4000059

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7691 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7691	likely pathogenic
REVEL	0.227	benign-leaning
SaProt	LLR -7.92	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 30 kb · p 4.9e-09 · regional, not allelic
Overall
CADD	23.6	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.0013% 21/1,614,102 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.00333%	30,005
South Asian	0.0022%	45,543
European (non-Finnish)	0.00136%	73,753

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: CEBPZ
Protein: p.Phe220Leu
Coding: c.658T>C
MANE Select: NM_005760
Type: single nucleotide variant
Location: chr2:37228535 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.34

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

Similar variants

CEBPZ p.Ala1008Thr Uncertain significance ★ ⚠ same type
CEBPZ p.Ala2Ser Uncertain significance ★ ⚠ same type
CEBPZ p.Ala2Val Uncertain significance ★ ⚠ same type
CEBPZ p.Ala365Val Uncertain significance ★ ⚠ same type
CEBPZ p.Ala369Ser Uncertain significance ★ ⚠ same type
CEBPZ p.Ala382Val Uncertain significance ★ ⚠ same type
CEBPZ p.Ala3Ser Uncertain significance ★ ⚠ same type
CEBPZ p.Ala3Val 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/cebpz-p-phe220leu (accessed [today's date]).

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