Is LAMB3 p.Arg552His (c.1655G>A) pathogenic?

LAMB3 p.Arg552His (c.1655G>A) is classified Uncertain significance in LAMB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-20). AlphaMissense: likely benign (0.0736); Very rare (popmax 0.00891%, eas); Associated with junctional epidermolysis bullosa Herlitz type.

What condition is associated with LAMB3 p.Arg552His (c.1655G>A)?

LAMB3 p.Arg552His (c.1655G>A) is associated with junctional epidermolysis bullosa Herlitz type, amelogenesis imperfecta type 1A, junctional epidermolysis bullosa, non-Herlitz type (ClinVar).

How common is LAMB3 p.Arg552His (c.1655G>A) in the general population?

LAMB3 p.Arg552His (c.1655G>A) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about LAMB3 p.Arg552His (c.1655G>A)?

AlphaMissense predicts likely benign (score 0.0736) — an in-silico prediction, not a clinical call.

LAMB3 p.Arg552His

Q: How is Severe generalized junctional epidermolysis bullosa inherited?

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

c.1655G>A · VCV3891562

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0736 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

junctional epidermolysis bullosa Herlitz type

Computational evidence

Protein change
AlphaMissense	0.0736	likely benign
REVEL	0.153	moderately benign-leaning
SaProt	LLR -7.15	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.42	GERP -3.2, phastCons 0.001
Regional constraint	o/e 0.97	unconstrained · MANE · 36 kb · p 0.27 · regional, not allelic
Overall
CADD	18.13	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,872 alleles

Filtering AF 0.00503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00463%

Overall 0.00508% 82/1,613,666 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,218
European (non-Finnish)	0.00619%	16,161
South Asian	0.0022%	45,523
Admixed American	0.00167%	60,008
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00133%	75,056

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.Arg552His
Coding: c.1655G>A
MANE Select: NM_000228
Type: single nucleotide variant
Location: chr1:209625969 (GRCh38)
Gene constraint: LOEUF 0.829 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.55
Residue 552: a disulfide bond; the laminin egf-like 6 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

Also linked: amelogenesis imperfecta type 1A junctional epidermolysis bullosa, non-Herlitz type

For Severe generalized junctional epidermolysis bullosa (Orphanet):

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

Similar variants

LAMB3 p.Arg552Cys 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
LAMB3 c.28+1G>T 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-arg552his (accessed [today's date]).

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