Is LAMB3 p.Arg135= (c.405C>T) pathogenic?

LAMB3 p.Arg135= (c.405C>T) is classified Conflicting classifications of pathogenicity in LAMB3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-02-03). Ultra-rare (popmax 0.0164%, mid); Associated with junctional epidermolysis bullosa, non-Herlitz type.

What condition is associated with LAMB3 p.Arg135= (c.405C>T)?

LAMB3 p.Arg135= (c.405C>T) is associated with junctional epidermolysis bullosa, non-Herlitz type, junctional epidermolysis bullosa Herlitz type (ClinVar).

How common is LAMB3 p.Arg135= (c.405C>T) in the general population?

LAMB3 p.Arg135= (c.405C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

LAMB3 p.Arg135=

c.405C>T · rs1007125449 · VCV793268

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

junctional epidermolysis bullosa, non-Herlitz type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.4	GERP -1.3, phastCons 1
Overall
CADD	10.96	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.00062% 10/1,613,960 alleles · ultra-rare exomes 9/1,461,822 · genomes 1/152,138 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.00133%	74,928
European (non-Finnish)	0.000678%	147,500

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.Arg135=
Coding: c.405C>T
MANE Select: NM_000228
dbSNP: rs1007125449
Type: single nucleotide variant
Location: chr1:209634606 (GRCh38)
Gene constraint: LOEUF 0.829 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.55
Residue 135: the laminin n-terminal domain

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

Disease context

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

Also linked: junctional epidermolysis bullosa Herlitz type

Similar variants

LAMB3 p.Arg135His Uncertain significance ★★ ⚠ same residue
LAMB3 p.Arg135Cys Uncertain significance ★ ⚠ same residue
LAMB3 c.1132+5G>A Pathogenic/Likely pathogenic ★★ same condition
LAMB3 c.1133-22G>A Pathogenic ★★ same condition
LAMB3 c.1288+1G>T Pathogenic/Likely pathogenic ★★ same condition
LAMB3 c.1486-1G>A Likely pathogenic ★★ same condition
LAMB3 c.1597+1G>T Likely pathogenic ★★ same condition
LAMB3 c.2701+2T>C 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-arg135 (accessed [today's date]).

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