Is LAMB3 p.Ser608fs (c.1823dup) pathogenic?

LAMB3 p.Ser608fs (c.1823dup) is classified Pathogenic in LAMB3 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-11-02). Very rare (popmax 0.00667%, afr); Associated with junctional epidermolysis bullosa Herlitz type.

What condition is associated with LAMB3 p.Ser608fs (c.1823dup)?

LAMB3 p.Ser608fs (c.1823dup) is associated with junctional epidermolysis bullosa Herlitz type (ClinVar).

How common is LAMB3 p.Ser608fs (c.1823dup) in the general population?

LAMB3 p.Ser608fs (c.1823dup) is very rare (popmax 0.00667%, afr) (gnomAD).

LAMB3 p.Ser608fs

Q: How is Severe generalized junctional epidermolysis bullosa inherited?

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

c.1823dup · rs1057516219 · VCV370083

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

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 14 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.2	GERP 0.79, phastCons 1
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% African / African-American · 5/74,944 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.000372% 6/1,614,044 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,989
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Ser608fs
Coding: c.1823dup
MANE Select: NM_000228
dbSNP: rs1057516219
Type: Duplication
Location: chr1:209625800 (GRCh38)
Gene constraint: LOEUF 0.829 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.55
Residue 608: the 'domain ii' region

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.Asn345fs Pathogenic ★★ same condition
LAMB3 p.Leu11fs Pathogenic/Likely pathogenic ★★ same condition
LAMB3 p.Ser155fs Pathogenic/Likely pathogenic ★★ same condition
LAMB3 c.2702-12dup Benign ★★ same condition
LAMB3 c.28+2dup Likely pathogenic ★ same condition
LAMB3 p.Ser800fs Likely pathogenic same condition
LAMB3 c.822+2dup Uncertain significance same condition
LAMB3 p.Asn487dup 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/lamb3-p-ser608fs (accessed [today's date]).

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