Is BCL11B p.Pro666= (c.1998C>T) pathogenic?

BCL11B p.Pro666= (c.1998C>T) is classified Likely benign in BCL11B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-28). Very rare (popmax 9.64e-05%, nfe).

How common is BCL11B p.Pro666= (c.1998C>T) in the general population?

BCL11B p.Pro666= (c.1998C>T) is very rare (popmax 9.64e-05%, nfe) (gnomAD).

BCL11B p.Pro666=

c.1998C>T · rs775842333 · VCV3017292

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 9.64e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.4	GERP -3.6
Overall
CADD	5.344	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.64e-05% European (non-Finnish) · 1/1,037,294 alleles

Overall 0.000151% 2/1,323,528 alleles · very rare exomes 2/1,174,580 · genomes 0/148,948 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00204%	48,988
European (non-Finnish)grpmax	9.64e-05%	1,037,294

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: BCL11B
Protein: p.Pro666=
Coding: c.1998C>T
MANE Select: NM_138576
dbSNP: rs775842333
Type: single nucleotide variant
Location: chr14:99174838 (GRCh38)
Gene constraint: LOEUF 0.462 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 51.76 · 6 PDB
Residue 666: a UniProt-annotated variant site (in iddsfta); the 'disordered' region

Full BCL11B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BCL11B p.Pro666Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
BCL11B p.Pro666_Gly667insGluProPhePro Uncertain significance ★ same residue
BCL11B p.Asn807Lys Pathogenic/Likely pathogenic ★★ ⚠ same type
BCL11B p.Cys808Arg Likely pathogenic ★★ same type
BCL11B p.Tyr824Ter Likely pathogenic ★★ same type
BCL11B p.Ala152Val Uncertain significance ★★ ⚠ same type
BCL11B p.Ala188Thr Uncertain significance ★★ ⚠ same type
BCL11B p.Ala339Val 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/bcl11b-p-pro666 (accessed [today's date]).

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