Is LAMB3 p.Val458Ala (c.1373T>C) pathogenic?

LAMB3 p.Val458Ala (c.1373T>C) is classified Uncertain significance in LAMB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-06). AlphaMissense: likely benign (0.0804); Very rare (popmax 0.00119%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LAMB3 p.Val458Ala (c.1373T>C)?

LAMB3 p.Val458Ala (c.1373T>C) is associated with Inborn genetic diseases (ClinVar).

How common is LAMB3 p.Val458Ala (c.1373T>C) in the general population?

LAMB3 p.Val458Ala (c.1373T>C) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about LAMB3 p.Val458Ala (c.1373T>C)?

AlphaMissense predicts likely benign (score 0.0804) — an in-silico prediction, not a clinical call.

LAMB3 p.Val458Ala

c.1373T>C · rs201559735 · VCV3117611

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0804 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0804	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -7.99	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 7	GERP -0.26, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 36 kb · p 0.27 · regional, not allelic
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00119% European (non-Finnish) · 14/1,180,024 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000867% 14/1,613,942 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: LAMB3
Protein: p.Val458Ala
Coding: c.1373T>C
MANE Select: NM_000228
dbSNP: rs201559735
Type: single nucleotide variant
Location: chr1:209627495 (GRCh38)
Gene constraint: LOEUF 0.829 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.55
Residue 458: a disulfide bond; the laminin egf-like 4 domain

Full LAMB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LAMB3 p.Ala1071Thr Uncertain significance ★★ ⚠ same condition
LAMB3 p.Ala1145Val Uncertain significance ★★ ⚠ same condition
LAMB3 p.Ala330Thr Uncertain significance ★★ ⚠ same condition
LAMB3 p.Ala330Val Uncertain significance ★★ ⚠ same condition
LAMB3 p.Ala590Val Uncertain significance ★★ ⚠ same condition
LAMB3 p.Ala825Thr Uncertain significance ★★ ⚠ same condition
LAMB3 p.Ala832Val Uncertain significance ★★ ⚠ same condition
LAMB3 p.Ala855Gly 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/lamb3-p-val458ala (accessed [today's date]).

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