Is LAMC3 p.Pro731Ser (c.2191C>T) pathogenic?

LAMC3 p.Pro731Ser (c.2191C>T) is classified Uncertain significance in LAMC3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-17). AlphaMissense: likely benign (0.1026); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LAMC3 p.Pro731Ser (c.2191C>T)?

LAMC3 p.Pro731Ser (c.2191C>T) is associated with Inborn genetic diseases (ClinVar).

How common is LAMC3 p.Pro731Ser (c.2191C>T) in the general population?

LAMC3 p.Pro731Ser (c.2191C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about LAMC3 p.Pro731Ser (c.2191C>T)?

AlphaMissense predicts likely benign (score 0.1026) — an in-silico prediction, not a clinical call.

LAMC3 p.Pro731Ser

c.2191C>T · rs1196109015 · VCV1376329

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1026 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1026	likely benign
REVEL	0.193	benign-leaning
SaProt	LLR -7.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.41	acceptor gain · deltas
Pangolin	Δ0.36	loss · gain 0.34 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 3.9	GERP 0.95, phastCons 0.7
Regional constraint	o/e 0.94	unconstrained · MANE · 83 kb · p 0.0039 · regional, not allelic
Overall
CADD	22.1	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 0.000254% European (non-Finnish) · 3/1,180,024 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,152 alleles · very rare exomes 3/1,461,840 · genomes 0/152,312 · joint denominator

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.Pro731Ser
Coding: c.2191C>T
MANE Select: NM_006059
dbSNP: rs1196109015
Type: single nucleotide variant
Location: chr9:131061067 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.23
Residue 731: the laminin egf-like 6 domain

Full LAMC3 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

Similar variants

LAMC3 p.Gln550Ter Pathogenic ★★ same condition
LAMC3 p.Ser421Ter Pathogenic ★★ same condition
LAMC3 p.Ala109Pro Uncertain significance ★★ ⚠ same condition
LAMC3 p.Ala1137Pro Uncertain significance ★★ ⚠ same condition
LAMC3 p.Ala1137Thr Uncertain significance ★★ ⚠ same condition
LAMC3 p.Ala1161Val Uncertain significance ★★ ⚠ same condition
LAMC3 p.Ala1183Thr Uncertain significance ★★ ⚠ same condition
LAMC3 p.Ala1244Thr Uncertain significance ★★ ⚠ 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/lamc3-p-pro731ser (accessed [today's date]).

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