Is BCL11A p.Leu22Pro (c.65T>C) pathogenic?

BCL11A p.Leu22Pro (c.65T>C) is classified Uncertain significance in BCL11A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-16). AlphaMissense: likely benign (0.1383); Very rare (popmax 0.00334%, amr); Associated with Inborn genetic diseases.

What condition is associated with BCL11A p.Leu22Pro (c.65T>C)?

BCL11A p.Leu22Pro (c.65T>C) is associated with Inborn genetic diseases (ClinVar).

How common is BCL11A p.Leu22Pro (c.65T>C) in the general population?

BCL11A p.Leu22Pro (c.65T>C) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about BCL11A p.Leu22Pro (c.65T>C)?

AlphaMissense predicts likely benign (score 0.1383) — an in-silico prediction, not a clinical call.

BCL11A p.Leu22Pro

c.65T>C · rs766722791 · VCV2393891

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1383 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1383	likely benign
REVEL	0.273	benign-leaning
SaProt	LLR -6.11	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 11	GERP 2.6, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 91 kb · p 2.1e-08 · regional, not allelic
Overall
CADD	24.1	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 0.00334% Admixed American · 2/59,950 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00186% 30/1,612,876 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,975
European (non-Finnish)	0.00229%	43,672
African / African-American	0.00134%	74,874

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: BCL11A
Protein: p.Leu22Pro
Coding: c.65T>C
MANE Select: NM_022893
dbSNP: rs766722791
Type: single nucleotide variant
Location: chr2:60546291 (GRCh38)
Gene constraint: LOEUF 0.125 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.09 · 17 PDB
Residue 22: the 'required for nuclear body formation and for sumo1 recruitment' region; the 'disordered' region

Full BCL11A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BCL11A p.Leu22Val Uncertain significance ★ ⚠ same residue
BCL11A p.Gly610Ser Uncertain significance ★★ ⚠ same condition
BCL11A p.Leu360Val Uncertain significance ★★ ⚠ same condition
BCL11A p.Pro730Thr Uncertain significance ★★ ⚠ same condition
BCL11A p.Val602Ile Uncertain significance ★★ ⚠ same condition
BCL11A c.55+1G>A Likely pathogenic ★ same condition
BCL11A c.56-1G>C Pathogenic ★ same condition
BCL11A p.Ala255Val Uncertain significance ★ ⚠ same condition

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/bcl11a-p-leu22pro (accessed [today's date]).

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