Is LAMC3 p.Ser519fs (c.1553dup) pathogenic?

LAMC3 p.Ser519fs (c.1553dup) is classified Pathogenic in LAMC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-09). Very rare (popmax 0.00587%, amr).

How common is LAMC3 p.Ser519fs (c.1553dup) in the general population?

LAMC3 p.Ser519fs (c.1553dup) is very rare (popmax 0.00587%, amr) (gnomAD).

LAMC3 p.Ser519fs

c.1553dup · rs1564375476 · VCV1908192

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00587%, amr)

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 9 of 28
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -8.2	GERP -3.8
Overall
CADD	18.29	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 0.00587% Admixed American · 3/51,072 alleles

Filtering AF 0.00156% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000832%

Overall 0.000387% 6/1,550,930 alleles · very rare exomes 5/1,398,978 · genomes 1/151,952 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00587%	17,024
African / African-American	0.00137%	72,982
European (non-Finnish)	0.000174%	573,293

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: LAMC3
Protein: p.Ser519fs
Coding: c.1553dup
MANE Select: NM_006059
dbSNP: rs1564375476
Type: Duplication
Location: chr9:131049047 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.23
Residue 519: the laminin iv type a domain

Full LAMC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LAMC3 p.Ser519= Likely benign ★ same residue
LAMC3 p.Val112fs Pathogenic ★★ same type
LAMC3 p.Ala1170_Ala1175dup Uncertain significance ★★ same type
LAMC3 p.Gln1011fs Pathogenic ★ same type
LAMC3 p.Gln524fs Pathogenic ★ same type
LAMC3 p.Gln781fs Pathogenic ★ same type
LAMC3 p.Gly567fs Pathogenic ★ same type
LAMC3 p.Gly795fs Pathogenic ★ same type

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/lamc3-p-ser519fs (accessed [today's date]).

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