Is LBR p.Ala7= (c.21C>T) pathogenic?

LBR p.Ala7= (c.21C>T) is classified Conflicting classifications of pathogenicity in LBR (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-19). Ultra-rare (popmax 0.033%, mid); Associated with Greenberg dysplasia.

What condition is associated with LBR p.Ala7= (c.21C>T)?

LBR p.Ala7= (c.21C>T) is associated with Greenberg dysplasia (ClinVar).

How common is LBR p.Ala7= (c.21C>T) in the general population?

LBR p.Ala7= (c.21C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

How is Greenberg dysplasia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

LBR p.Ala7=

c.21C>T · rs184378202 · VCV295950

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

Greenberg dysplasia

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 -5.2	GERP -4.9
Overall
CADD	2.001	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.0057% 92/1,613,954 alleles · ultra-rare exomes 83/1,461,824 · genomes 9/152,130 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
South Asian	0.0121%	8,279
East Asian	0.0111%	8,978
Remaining individualsnot grpmax-eligible	0.008%	12,501
Admixed American	0.00667%	15,002
African / African-American	0.00534%	18,742
European (non-Finnish)	0.00517%	19,344

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: LBR
Protein: p.Ala7=
Coding: c.21C>T
MANE Select: NM_002296
dbSNP: rs184378202
Type: single nucleotide variant
Location: chr1:225424055 (GRCh38)
Gene constraint: LOEUF 0.499 · pLI 0.97 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.89 · 1 PDB
Residue 7: the tudor domain

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

Disease context

Greenberg dysplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Greenberg dysplasia (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Neonatal

Similar variants

LBR p.Arg512Gln Pathogenic/Likely pathogenic ★★ same condition
LBR p.Arg583Gln Pathogenic ★★ same condition
LBR p.Arg586His Pathogenic/Likely pathogenic ★★ same condition
LBR p.Asn547Asp Pathogenic/Likely pathogenic ★★ same condition
LBR p.Asn547Ser Pathogenic/Likely pathogenic ★★ same condition
LBR c.*1586G>A Uncertain significance ★★ same condition
LBR p.Ala521Ser Uncertain significance ★★ ⚠ same condition
LBR p.Ala521Thr 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/lbr-p-ala7 (accessed [today's date]).

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