Is CBFA2T3 p.Glu533Lys (c.1597G>A) pathogenic?

CBFA2T3 p.Glu533Lys (c.1597G>A) is classified Uncertain significance in CBFA2T3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-13). AlphaMissense: ambiguous (0.4311); Very rare (popmax 0.00187%, nfe).

How common is CBFA2T3 p.Glu533Lys (c.1597G>A) in the general population?

CBFA2T3 p.Glu533Lys (c.1597G>A) is very rare (popmax 0.00187%, nfe) (gnomAD).

What do computational predictors say about CBFA2T3 p.Glu533Lys (c.1597G>A)?

AlphaMissense predicts ambiguous (score 0.4311) — an in-silico prediction, not a clinical call.

CBFA2T3 p.Glu533Lys

c.1597G>A · VCV4648721

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4311 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00187%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4311	ambiguous
REVEL	0.293	indeterminate
SaProt	LLR -12.57	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 0.00027 · regional, not allelic
Overall
CADD	29.4	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 0.00187% European (non-Finnish) · 22/1,179,024 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00149% 24/1,611,610 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00187%	53,592
Admixed American	0.00167%	59,964
Remaining individualsnot grpmax-eligible	0.0016%	62,396

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: CBFA2T3
Protein: p.Glu533Lys
Coding: c.1597G>A
MANE Select: NM_005187
Type: single nucleotide variant
Location: chr16:88879335 (GRCh38)
Gene constraint: LOEUF 0.957 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.26 · 1 PDB
Residue 533: the 'nervy homology region 3 (nhr3); essential for down-regulation of pfkfb3, pfkfb4 and pdk1 expression' region

Full CBFA2T3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CBFA2T3 p.Ala441Thr Likely benign ★★ same type
CBFA2T3 p.Ala534= Benign ★★ same type
CBFA2T3 p.Ala141Val Uncertain significance ★ ⚠ same type
CBFA2T3 p.Ala272Thr Uncertain significance ★ ⚠ same type
CBFA2T3 p.Ala350Thr Uncertain significance ★ ⚠ same type
CBFA2T3 p.Ala449Thr Uncertain significance ★ ⚠ same type
CBFA2T3 p.Ala451Thr Uncertain significance ★ ⚠ same type
CBFA2T3 p.Ala460Pro 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/cbfa2t3-p-glu533lys (accessed [today's date]).

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