Is LAMC2 p.Arg223Ter (c.667C>T) pathogenic?

LAMC2 p.Arg223Ter (c.667C>T) is classified Pathogenic in LAMC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-03-23). Very rare (popmax 0.000254%, nfe); Associated with epidermolysis bullosa, junctional 3A, intermediate.

What condition is associated with LAMC2 p.Arg223Ter (c.667C>T)?

LAMC2 p.Arg223Ter (c.667C>T) is associated with epidermolysis bullosa, junctional 3A, intermediate, junctional epidermolysis bullosa Herlitz type, epidermolysis bullosa, junctional 3B, severe (ClinVar).

How common is LAMC2 p.Arg223Ter (c.667C>T) in the general population?

LAMC2 p.Arg223Ter (c.667C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

LAMC2 p.Arg223Ter

c.667C>T · rs753268823 · VCV188791

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

epidermolysis bullosa, junctional 3A, intermediate

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 23
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.22	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 5.1	GERP 0.54, phastCons 1
Overall
CADD	36.0	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 0.000254% European (non-Finnish) · 3/1,179,998 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,846 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: LAMC2
Protein: p.Arg223Ter
Coding: c.667C>T
MANE Select: NM_005562
dbSNP: rs753268823
Type: single nucleotide variant
Location: chr1:183222115 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 72.89
Residue 223: the laminin iv type a domain

Full LAMC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

epidermolysis bullosa, junctional 3A, intermediate — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: junctional epidermolysis bullosa Herlitz type epidermolysis bullosa, junctional 3B, severe

Similar variants

LAMC2 c.1715-2A>G Likely pathogenic ★★ same condition
LAMC2 c.268+1G>A Likely pathogenic ★★ same condition
LAMC2 c.3328+1G>A Pathogenic/Likely pathogenic ★★ same condition
LAMC2 c.640+1G>A Likely pathogenic ★★ same condition
LAMC2 p.Arg1129Ter Pathogenic ★★ same condition
LAMC2 p.Arg115Ter Pathogenic ★★ same condition
LAMC2 p.Arg245Ter Pathogenic/Likely pathogenic ★★ same condition
LAMC2 p.Arg349Ter 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/lamc2-p-arg223ter (accessed [today's date]).

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