Is LAMC2 p.Ile447Val (c.1339A>G) pathogenic?

LAMC2 p.Ile447Val (c.1339A>G) is classified Uncertain significance in LAMC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-03-22). AlphaMissense: likely benign (0.0628); Rare (popmax 0.104%, afr); Associated with Inborn genetic diseases.

What condition is associated with LAMC2 p.Ile447Val (c.1339A>G)?

LAMC2 p.Ile447Val (c.1339A>G) is associated with Inborn genetic diseases, junctional epidermolysis bullosa Herlitz type, epidermolysis bullosa, junctional 3A, intermediate (ClinVar).

How common is LAMC2 p.Ile447Val (c.1339A>G) in the general population?

LAMC2 p.Ile447Val (c.1339A>G) is rare (popmax 0.104%, afr) (gnomAD).

What do computational predictors say about LAMC2 p.Ile447Val (c.1339A>G)?

AlphaMissense predicts likely benign (score 0.0628) — an in-silico prediction, not a clinical call.

LAMC2 p.Ile447Val

c.1339A>G · rs149828888 · VCV2307044

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0628 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.104%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0628	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -4.35	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 0.32	GERP -3.8, phastCons 0.56
Regional constraint	o/e 0.92	unconstrained · MANE · 45 kb · p 0.031 · regional, not allelic
Overall
CADD	4.604	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 0.104% African / African-American · 78/74,988 alleles

Filtering AF 0.0854% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0786%

Overall 0.00781% 126/1,614,074 alleles · rare exomes 74/1,461,882 · genomes 52/152,192 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.104%	961
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,701
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0144%	6,946
Admixed American	0.0133%	7,503
South Asian	0.0022%	45,537
European (non-Finnish)	0.00169%	59,001

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.Ile447Val
Coding: c.1339A>G
MANE Select: NM_005562
dbSNP: rs149828888
Type: single nucleotide variant
Location: chr1:183227568 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 72.89
Residue 447: the laminin egf-like 5 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

LAMC2 p.Ile447Thr Uncertain significance ★ ⚠ same residue
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.Arg223Ter 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-ile447val (accessed [today's date]).

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