Is LAMC2 p.Arg533Pro (c.1598G>C) pathogenic?

LAMC2 p.Arg533Pro (c.1598G>C) is classified Uncertain significance in LAMC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: likely benign (0.0839); Very rare (popmax 0.005%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LAMC2 p.Arg533Pro (c.1598G>C)?

LAMC2 p.Arg533Pro (c.1598G>C) is associated with Inborn genetic diseases (ClinVar).

How common is LAMC2 p.Arg533Pro (c.1598G>C) in the general population?

LAMC2 p.Arg533Pro (c.1598G>C) is very rare (popmax 0.005%, nfe) (gnomAD).

What do computational predictors say about LAMC2 p.Arg533Pro (c.1598G>C)?

AlphaMissense predicts likely benign (score 0.0839) — an in-silico prediction, not a clinical call.

LAMC2 p.Arg533Pro

c.1598G>C · VCV4623509

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0839 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0839	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -8.56	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 -1.2	GERP -4.4
Regional constraint	o/e 0.92	unconstrained · MANE · 45 kb · p 0.031 · regional, not allelic
Overall
CADD	16.86	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 0.005% European (non-Finnish) · 59/1,180,004 alleles

Filtering AF 0.00394% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00361%

Overall 0.00397% 64/1,613,726 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.005%	20,000
Remaining individualsnot grpmax-eligible	0.0048%	20,824
African / African-American	0.00267%	37,407

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.Arg533Pro
Coding: c.1598G>C
MANE Select: NM_005562
Type: single nucleotide variant
Location: chr1:183228503 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 72.89
Residue 533: the laminin egf-like 7 domain; a disulfide bond

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

Similar variants

LAMC2 p.Arg533Gln Uncertain significance ★ ⚠ same residue
LAMC2 p.Arg533Trp Uncertain significance ★ ⚠ same residue
LAMC2 p.Arg533= Likely benign ★ same residue
LAMC2 p.Asp247His Uncertain significance ★★ ⚠ same condition
LAMC2 p.Gln1005Arg Uncertain significance ★★ ⚠ same condition
LAMC2 p.Glu1160Asp Uncertain significance ★★ ⚠ same condition
LAMC2 p.Gly278Arg Uncertain significance ★★ ⚠ same condition
LAMC2 p.Gly672Ala 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/lamc2-p-arg533pro (accessed [today's date]).

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