Is CBFA2T3 p.Pro84Leu (c.251C>T) pathogenic?

CBFA2T3 p.Pro84Leu (c.251C>T) is classified Uncertain significance in CBFA2T3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). AlphaMissense: likely benign (0.0765); Rare (popmax 0.213%, mid).

How common is CBFA2T3 p.Pro84Leu (c.251C>T) in the general population?

CBFA2T3 p.Pro84Leu (c.251C>T) is rare (popmax 0.213%, mid) (gnomAD).

What do computational predictors say about CBFA2T3 p.Pro84Leu (c.251C>T)?

AlphaMissense predicts likely benign (score 0.0765) — an in-silico prediction, not a clinical call.

CBFA2T3 p.Pro84Leu

c.251C>T · rs201395224 · VCV2588950

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0765 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.213%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0765	likely benign
REVEL	0.271	benign-leaning
SaProt	LLR -7.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.3	GERP 0.52, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 0.00027 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.213% Middle Eastern · 12/5,646 alleles

Filtering AF 0.123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0961%

Overall 0.0254% 374/1,474,058 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.213%	470
Ashkenazi Jewishnot grpmax-eligible	0.135%	742
Remaining individualsnot grpmax-eligible	0.0281%	3,564
European (non-Finnish)	0.0256%	3,908
Admixed American	0.0224%	4,468
South Asian	0.0222%	4,513
East Asian	0.0027%	36,984
African / African-American	0.00149%	67,330

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.Pro84Leu
Coding: c.251C>T
MANE Select: NM_005187
dbSNP: rs201395224
Type: single nucleotide variant
Location: chr16:88901557 (GRCh38)
Gene constraint: LOEUF 0.957 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.26 · 1 PDB
Residue 84: the 'mediates localization to the nucleus' region; the 'mediates interaction with pde7a (in isoform 2)' region; the 'required for nucleolar targeting (in isoform 1)' region; the 'disordered' region

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

Similar variants

CBFA2T3 p.Pro84= Likely benign ★ same residue
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

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-pro84leu (accessed [today's date]).

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