Is LAMB1 p.Arg152Pro (c.455G>C) pathogenic?

LAMB1 p.Arg152Pro (c.455G>C) is classified Uncertain significance in LAMB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-26). AlphaMissense: likely pathogenic (0.9987); Very rare (popmax 0.00442%, sas); Associated with cobblestone lissencephaly without muscular or ocular involvement.

What condition is associated with LAMB1 p.Arg152Pro (c.455G>C)?

LAMB1 p.Arg152Pro (c.455G>C) is associated with cobblestone lissencephaly without muscular or ocular involvement (ClinVar).

How common is LAMB1 p.Arg152Pro (c.455G>C) in the general population?

LAMB1 p.Arg152Pro (c.455G>C) is very rare (popmax 0.00442%, sas) (gnomAD).

What do computational predictors say about LAMB1 p.Arg152Pro (c.455G>C)?

AlphaMissense predicts likely pathogenic (score 0.9987) — an in-silico prediction, not a clinical call.

LAMB1 p.Arg152Pro

Q: How is Cobblestone lissencephaly without muscular or ocular involvement inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.455G>C · rs778475293 · VCV3065143

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9987 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00442%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cobblestone lissencephaly without muscular or ocular involvement

Computational evidence

Protein change
AlphaMissense	0.9987	likely pathogenic · top 2% in LAMB1
REVEL	0.937	strongly pathogenic-leaning
SaProt	LLR -16.46	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 79 kb · p 0.15 · regional, not allelic
Overall
CADD	32.0	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 0.00442% South Asian · 4/90,532 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000895%

Overall 0.000275% 4/1,455,228 alleles · very rare

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: LAMB1
Protein: p.Arg152Pro
Coding: c.455G>C
MANE Select: NM_002291
dbSNP: rs778475293
Type: single nucleotide variant
Location: chr7:107986332 (GRCh38)
Gene constraint: LOEUF 0.601 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.99 · 3 PDB
Residue 152: the laminin n-terminal domain

Full LAMB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cobblestone lissencephaly without muscular or ocular involvement — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Cobblestone lissencephaly without muscular or ocular involvement (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

LAMB1 c.4188+1G>C Pathogenic/Likely pathogenic ★★ same condition
LAMB1 p.Arg397Ter Pathogenic ★★ same condition
LAMB1 c.1985+5G>T Uncertain significance ★★ same condition
LAMB1 p.Arg633Pro Uncertain significance ★★ ⚠ same condition
LAMB1 p.Arg795Gln Uncertain significance ★★ ⚠ same condition
LAMB1 p.Arg801Lys Uncertain significance ★★ ⚠ same condition
LAMB1 p.Asn757Thr Uncertain significance ★★ ⚠ same condition
LAMB1 p.Glu1395Lys 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/lamb1-p-arg152pro (accessed [today's date]).

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