Is LAMC2 p.Ser283Pro (c.847T>C) pathogenic?

LAMC2 p.Ser283Pro (c.847T>C) is classified Uncertain significance in LAMC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-02). AlphaMissense: likely pathogenic (0.5938); Very rare (popmax 0.00667%, afr).

How common is LAMC2 p.Ser283Pro (c.847T>C) in the general population?

LAMC2 p.Ser283Pro (c.847T>C) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about LAMC2 p.Ser283Pro (c.847T>C)?

AlphaMissense predicts likely pathogenic (score 0.5938) — an in-silico prediction, not a clinical call.

LAMC2 p.Ser283Pro

c.847T>C · rs763119021 · VCV1434895

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5938 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.5938	likely pathogenic
REVEL	0.326	indeterminate
SaProt	LLR -11.69	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 45 kb · p 0.031 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00667% African / African-American · 5/74,932 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00031% 5/1,614,078 alleles · very rare exomes 2/1,461,872 · genomes 3/152,206 · 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: LAMC2
Protein: p.Ser283Pro
Coding: c.847T>C
MANE Select: NM_005562
dbSNP: rs763119021
Type: single nucleotide variant
Location: chr1:183223218 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 72.89
Residue 283: the laminin iv type a domain

Full LAMC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LAMC2 c.1715-2A>G Likely pathogenic ★★ same type
LAMC2 c.268+1G>A Likely pathogenic ★★ same type
LAMC2 c.3328+1G>A Pathogenic/Likely pathogenic ★★ same type
LAMC2 c.640+1G>A Likely pathogenic ★★ same type
LAMC2 p.Arg1129Ter Pathogenic ★★ same type
LAMC2 p.Arg115Ter Pathogenic ★★ same type
LAMC2 p.Arg170Ter Pathogenic/Likely pathogenic ★★ same type
LAMC2 p.Arg223Ter Pathogenic ★★ same type

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-ser283pro (accessed [today's date]).

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