Is LAMC3 p.Pro326Ser (c.976C>T) pathogenic?

LAMC3 p.Pro326Ser (c.976C>T) is classified Conflicting classifications of pathogenicity in LAMC3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-22). AlphaMissense: likely benign (0.1078); Ultra-rare (popmax 0.0494%, mid); Associated with occipital pachygyria and polymicrogyria.

What condition is associated with LAMC3 p.Pro326Ser (c.976C>T)?

LAMC3 p.Pro326Ser (c.976C>T) is associated with occipital pachygyria and polymicrogyria (ClinVar).

How common is LAMC3 p.Pro326Ser (c.976C>T) in the general population?

LAMC3 p.Pro326Ser (c.976C>T) is ultra-rare (popmax 0.0494%, mid) (gnomAD).

What do computational predictors say about LAMC3 p.Pro326Ser (c.976C>T)?

AlphaMissense predicts likely benign (score 0.1078) — an in-silico prediction, not a clinical call.

LAMC3 p.Pro326Ser

c.976C>T · rs370821927 · VCV1429474

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1078 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

occipital pachygyria and polymicrogyria

Computational evidence

Protein change
AlphaMissense	0.1078	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -10.88	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -1.7, phastCons 0.99
Regional constraint	o/e 0.94	unconstrained · MANE · 83 kb · p 0.0039 · regional, not allelic
Overall
CADD	21.4	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 0.0494% Middle Eastern · 3/6,074 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00981%

Overall 0.00992% 160/1,612,532 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0494%	2,025
European (non-Finnish)	0.012%	8,306
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,856
Remaining individualsnot grpmax-eligible	0.0048%	20,814
Finnishnot grpmax-eligible	0.00474%	21,092
East Asian	0.00446%	22,440
African / African-American	0.00401%	24,953
South Asian	0.0011%	91,044

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.Pro326Ser
Coding: c.976C>T
MANE Select: NM_006059
dbSNP: rs370821927
Type: single nucleotide variant
Location: chr9:131036332 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.23
Residue 326: the laminin egf-like 1 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-pro326ser (accessed [today's date]).

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