Is LBR p.Leu331Phe (c.991C>T) pathogenic?

LBR p.Leu331Phe (c.991C>T) is classified Uncertain significance in LBR (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-26). AlphaMissense: likely benign (0.0837); Ultra-rare (popmax 0.0115%, nfe); Associated with Greenberg dysplasia.

What condition is associated with LBR p.Leu331Phe (c.991C>T)?

LBR p.Leu331Phe (c.991C>T) is associated with Greenberg dysplasia, connective tissue disorder (ClinVar).

How common is LBR p.Leu331Phe (c.991C>T) in the general population?

LBR p.Leu331Phe (c.991C>T) is ultra-rare (popmax 0.0115%, nfe) (gnomAD).

How is Greenberg dysplasia inherited?

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

What do computational predictors say about LBR p.Leu331Phe (c.991C>T)?

AlphaMissense predicts likely benign (score 0.0837) — an in-silico prediction, not a clinical call.

LBR p.Leu331Phe

c.991C>T · rs201609720 · VCV1702452

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0837 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0115%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Greenberg dysplasia

Computational evidence

Protein change
AlphaMissense	0.0837	likely benign
REVEL	0.336	indeterminate
SaProt	LLR -4.98	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.014	GERP -3.3
Regional constraint	o/e 0.94	unconstrained · MANE · 21 kb · p 0.12 · regional, not allelic
Overall
CADD	13.92	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 0.0115% European (non-Finnish) · 136/1,179,984 alleles

Filtering AF 0.00994% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00931%

Overall 0.00868% 140/1,613,546 alleles · ultra-rare exomes 129/1,461,852 · genomes 11/151,694 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0115%	8,676
Remaining individualsnot grpmax-eligible	0.0032%	31,237
Admixed American	0.00167%	59,934
African / African-American	0.00134%	74,738

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.Leu331Phe
Coding: c.991C>T
MANE Select: NM_002296
dbSNP: rs201609720
Type: single nucleotide variant
Location: chr1:225412547 (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 331: a UniProt-annotated variant site (in skpha)

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

Also linked: connective tissue disorder

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-leu331phe (accessed [today's date]).

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