Is LAMB3 p.Ser167fs (c.499_500del) pathogenic?

LAMB3 p.Ser167fs (c.499500del) is classified Pathogenic in LAMB3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-07-20). Very rare (popmax 0.0011%, sas); Associated with junctional epidermolysis bullosa Herlitz type.

What condition is associated with LAMB3 p.Ser167fs (c.499_500del)?

LAMB3 p.Ser167fs (c.499_500del) is associated with junctional epidermolysis bullosa Herlitz type (ClinVar).

How common is LAMB3 p.Ser167fs (c.499_500del) in the general population?

LAMB3 p.Ser167fs (c.499_500del) is very rare (popmax 0.0011%, sas) (gnomAD).

LAMB3 p.Ser167fs

Q: How is Severe generalized junctional epidermolysis bullosa inherited?

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

c.499_500del · rs1057516241 · VCV370111

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

junctional epidermolysis bullosa Herlitz type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.8	GERP -0.85, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,088 alleles

Overall 6.84e-05% 1/1,461,894 alleles · very rare

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: LAMB3
Protein: p.Ser167fs
Coding: c.499_500del
MANE Select: NM_000228
dbSNP: rs1057516241
Type: Microsatellite
Location: chr1:209634511 (GRCh38)
Gene constraint: LOEUF 0.829 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.55
Residue 167: the laminin n-terminal domain

Full LAMB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

junctional epidermolysis bullosa Herlitz type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Severe generalized junctional epidermolysis bullosa (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

LAMB3 p.Tyr146fs Pathogenic/Likely pathogenic ★★ same condition
LAMB3 p.Asp344fs Pathogenic ★ same condition
LAMB3 p.Cys401fs Likely pathogenic ★ same condition
LAMB3 p.Cys355_Glu356delinsTer Likely pathogenic same condition
LAMB3 p.Gly760_Gly761dup Uncertain significance same condition
LAMB3 p.Gly761dup Uncertain significance same condition
LAMB3 p.Ser167Arg Uncertain significance ⚠ same residue
LAMB3 c.1132+5G>A Pathogenic/Likely pathogenic ★★ 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/lamb3-p-ser167fs (accessed [today's date]).

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