Is LAMC3 p.Arg366Cys (c.1096C>T) pathogenic?

LAMC3 p.Arg366Cys (c.1096C>T) is classified Uncertain significance in LAMC3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.2022); Ultra-rare (popmax 0.0164%, mid).

How common is LAMC3 p.Arg366Cys (c.1096C>T) in the general population?

LAMC3 p.Arg366Cys (c.1096C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about LAMC3 p.Arg366Cys (c.1096C>T)?

AlphaMissense predicts likely benign (score 0.2022) — an in-silico prediction, not a clinical call.

LAMC3 p.Arg366Cys

c.1096C>T · rs756209261 · VCV1433876

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2022 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2022	likely benign
REVEL	0.397	indeterminate
SaProt	LLR -11.55	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.44	GERP -3.7, phastCons 0.037
Regional constraint	o/e 0.94	unconstrained · MANE · 83 kb · p 0.0039 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00285% 46/1,613,440 alleles · ultra-rare exomes 43/1,461,258 · genomes 3/152,182 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
East Asian	0.00446%	22,444
European (non-Finnish)	0.00314%	31,893
African / African-American	0.00267%	37,456
South Asian	0.0022%	45,539
Admixed American	0.00167%	60,004
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Arg366Cys
Coding: c.1096C>T
MANE Select: NM_006059
dbSNP: rs756209261
Type: single nucleotide variant
Location: chr9:131038983 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.23
Residue 366: the laminin egf-like 2 domain

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

Similar variants

LAMC3 p.Arg366His Uncertain significance ★ ⚠ same residue
LAMC3 c.1166-1G>A Likely pathogenic ★★ same type
LAMC3 c.3211+1G>A Likely pathogenic ★★ same type
LAMC3 c.3211+2T>C Likely pathogenic ★★ same type
LAMC3 c.976+1G>A Pathogenic ★★ same type
LAMC3 p.Cys810Ter Pathogenic ★★ same type
LAMC3 p.Gln550Ter Pathogenic ★★ same type
LAMC3 p.Ser421Ter 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-arg366cys (accessed [today's date]).

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