Is LAMC3 p.Pro522Ser (c.1564C>T) pathogenic?

LAMC3 p.Pro522Ser (c.1564C>T) is classified Benign in LAMC3 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0771); Common (popmax 31.7%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with occipital pachygyria and polymicrogyria.

What condition is associated with LAMC3 p.Pro522Ser (c.1564C>T)?

LAMC3 p.Pro522Ser (c.1564C>T) is associated with occipital pachygyria and polymicrogyria (ClinVar).

What do computational predictors say about LAMC3 p.Pro522Ser (c.1564C>T)?

AlphaMissense predicts likely benign (score 0.0771) — an in-silico prediction, not a clinical call.

LAMC3 p.Pro522Ser

Q: How common is LAMC3 p.Pro522Ser (c.1564C>T) in the general population?

LAMC3 p.Pro522Ser (c.1564C>T) is common (popmax 31.7%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1564C>T · rs869457 · VCV129451

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0771 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 31.7%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

occipital pachygyria and polymicrogyria

Computational evidence

Protein change
AlphaMissense	0.0771	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -5.93	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 3.7	GERP 0.87, phastCons 0.93
Regional constraint	o/e 0.94	unconstrained · MANE · 83 kb · p 0.0039 · regional, not allelic
Overall
CADD	12.93	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 31.7% European (non-Finnish) · 363,398/1,145,936 alleles

Filtering AF 31.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 31.6%

Overall 30.2% 467,563/1,550,350 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	33%	3
European (non-Finnish)grpmax	31.7%	3
Remaining individualsnot grpmax-eligible	29%	3
Middle Eastern	29%	3
South Asian	25%	4
East Asian	23.7%	4
African / African-American	23.4%	4
Ashkenazi Jewishnot grpmax-eligible	22.7%	4
Amishnot grpmax-eligible	22.2%	5
Admixed American	21%	5

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.Pro522Ser
Coding: c.1564C>T
MANE Select: NM_006059
dbSNP: rs869457
Type: single nucleotide variant
Location: chr9:131049064 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.23
Residue 522: a UniProt-annotated variant site (in); the laminin iv type a domain

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

Disease context

occipital pachygyria and polymicrogyria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LAMC3 c.1166-1G>A Likely pathogenic ★★ same condition
LAMC3 c.3211+2T>C Likely pathogenic ★★ same condition
LAMC3 p.Ala1090Thr Uncertain significance ★★ ⚠ same condition
LAMC3 p.Ala1163Thr Uncertain significance ★★ ⚠ same condition
LAMC3 p.Ala79Val Uncertain significance ★★ ⚠ same condition
LAMC3 p.Arg1167Gly Uncertain significance ★★ ⚠ same condition
LAMC3 p.Arg1205Trp Uncertain significance ★★ ⚠ same condition
LAMC3 p.Arg1351Trp 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-pro522ser (accessed [today's date]).

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