Is LBR p.Ser69Phe (c.206C>T) pathogenic?

LBR p.Ser69Phe (c.206C>T) is classified Uncertain significance in LBR (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-26). AlphaMissense: ambiguous (0.555); Ultra-rare (popmax 0.0269%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LBR p.Ser69Phe (c.206C>T)?

LBR p.Ser69Phe (c.206C>T) is associated with Inborn genetic diseases, Greenberg dysplasia (ClinVar).

How common is LBR p.Ser69Phe (c.206C>T) in the general population?

LBR p.Ser69Phe (c.206C>T) is ultra-rare (popmax 0.0269%, nfe) (gnomAD).

What do computational predictors say about LBR p.Ser69Phe (c.206C>T)?

AlphaMissense predicts ambiguous (score 0.555) — an in-silico prediction, not a clinical call.

LBR p.Ser69Phe

c.206C>T · rs369299493 · VCV295947

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.555 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0269%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.555	ambiguous
REVEL	0.604	indeterminate
SaProt	LLR -10.23	damaging
Splicing
SpliceAI	Δ0.34	acceptor gain · deltas
Pangolin	Δ0.28	gain · loss 0.16 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 21 kb · p 0.12 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0269% European (non-Finnish) · 317/1,180,042 alleles

Filtering AF 0.0244% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0234%

Overall 0.02% 322/1,613,764 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0269%	3,723
Remaining individualsnot grpmax-eligible	0.00801%	12,491

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.Ser69Phe
Coding: c.206C>T
MANE Select: NM_002296
dbSNP: rs369299493
Type: single nucleotide variant
Location: chr1:225422237 (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 69: the 'disordered' region

Full LBR 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

Also linked: Greenberg dysplasia

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.Ala109Gly Uncertain significance ★★ ⚠ same condition
LBR p.Ala434Ser 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-ser69phe (accessed [today's date]).

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