Is LAMC3 p.Phe623fs (c.1866del) pathogenic?

LAMC3 p.Phe623fs (c.1866del) is classified Pathogenic in LAMC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-08). Very rare (popmax 0.00134%, afr); Associated with LAMC3-related disorder.

What condition is associated with LAMC3 p.Phe623fs (c.1866del)?

LAMC3 p.Phe623fs (c.1866del) is associated with LAMC3-related disorder (ClinVar).

How common is LAMC3 p.Phe623fs (c.1866del) in the general population?

LAMC3 p.Phe623fs (c.1866del) is very rare (popmax 0.00134%, afr) (gnomAD).

LAMC3 p.Phe623fs

c.1866del · VCV4904968

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

LAMC3-related disorder

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 11 of 28
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.3	GERP -0.34, phastCons 1
Overall
CADD	23.2	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 0.00134% African / African-American · 1/74,674 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.0256% 413/1,613,242 alleles · very rare exomes 322/1,461,620 · genomes 91/151,622 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.625%	160
Remaining individualsnot grpmax-eligible	0.0032%	31,239
African / African-Americangrpmax	0.00134%	74,674
European (non-Finnish)	0.00102%	98,328

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe623fs
Coding: c.1866del
MANE Select: NM_006059
Type: Deletion
Location: chr9:131052887 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.23
Residue 623: the laminin iv type a domain

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

Disease context

LAMC3-related disorder

Similar variants

LAMC3 p.Pro779fs Pathogenic/Likely pathogenic ★★ same condition
LAMC3 p.Thr232fs Likely pathogenic ★ same condition
LAMC3 c.4231-12C>G Likely pathogenic ★ same condition
LAMC3 c.976+1G>C Conflicting classifications of pathogenicity ★ same condition
LAMC3 p.Gly795Trp Uncertain significance ★ ⚠ same condition
LAMC3 p.Gln1012= Likely benign same condition
LAMC3 c.809+2_809+8del Likely pathogenic ★★ same type
LAMC3 p.Asp1061fs Pathogenic/Likely 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-phe623fs (accessed [today's date]).

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