Is CBFA2T3 p.Pro2Leu (c.5C>T) pathogenic?

CBFA2T3 p.Pro2Leu (c.5C>T) is classified Uncertain significance in CBFA2T3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: likely benign (0.3038); Very rare (popmax 0.00475%, sas).

How common is CBFA2T3 p.Pro2Leu (c.5C>T) in the general population?

CBFA2T3 p.Pro2Leu (c.5C>T) is very rare (popmax 0.00475%, sas) (gnomAD).

What do computational predictors say about CBFA2T3 p.Pro2Leu (c.5C>T)?

AlphaMissense predicts likely benign (score 0.3038) — an in-silico prediction, not a clinical call.

CBFA2T3 p.Pro2Leu

c.5C>T · VCV4648714

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3038 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00475%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3038	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -6.80	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 -0.045	GERP -3.1
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 0.00027 · regional, not allelic
Overall
CADD	14.66	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 0.00475% South Asian · 4/84,268 alleles

Filtering AF 0.00161% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000947%

Overall 0.000714% 10/1,399,838 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00475%	21,067
Admixed American	0.00195%	51,222
Remaining individualsnot grpmax-eligible	0.00166%	60,124
European (non-Finnish)	0.000349%	286,728

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.Pro2Leu
Coding: c.5C>T
MANE Select: NM_005187
Type: single nucleotide variant
Location: chr16:88976803 (GRCh38)
Gene constraint: LOEUF 0.957 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.26 · 1 PDB
Residue 2: 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.Pro2Gln Uncertain significance ★ ⚠ 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-pro2leu (accessed [today's date]).

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