Is LAMC3 p.Ala321= (c.963C>T) pathogenic?

LAMC3 p.Ala321= (c.963C>T) is classified Benign in LAMC3 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 62.1%, eas) — too common for a highly-penetrant pathogenic allele; Associated with occipital pachygyria and polymicrogyria.

What condition is associated with LAMC3 p.Ala321= (c.963C>T)?

LAMC3 p.Ala321= (c.963C>T) is associated with occipital pachygyria and polymicrogyria (ClinVar).

LAMC3 p.Ala321=

Q: How common is LAMC3 p.Ala321= (c.963C>T) in the general population?

LAMC3 p.Ala321= (c.963C>T) is common (popmax 62.1%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.963C>T · rs2275131 · VCV129477

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 62.1%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

occipital pachygyria and polymicrogyria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 0.75, phastCons 1
Overall
CADD	10.52	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 62.1% East Asian · 27,835/44,812 alleles

Filtering AF 61.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 61.3%

Overall 46.8% 755,030/1,612,512 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	62.1%	2
Admixed American	52.4%	2
Ashkenazi Jewishnot grpmax-eligible	51.7%	2
European (non-Finnish)	49%	2
Remaining individualsnot grpmax-eligible	46.4%	2
Middle Eastern	42.6%	2
Finnishnot grpmax-eligible	41.7%	2
Amishnot grpmax-eligible	35.5%	3
South Asian	31.6%	3
African / African-American	20.7%	5

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.Ala321=
Coding: c.963C>T
MANE Select: NM_006059
dbSNP: rs2275131
Type: single nucleotide variant
Location: chr9:131036319 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.23
Residue 321: the laminin egf-like 1 domain; a disulfide bond

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-ala321 (accessed [today's date]).

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