Is LAMB3 p.Pro425Leu (c.1274C>T) pathogenic?

LAMB3 p.Pro425Leu (c.1274C>T) is classified Uncertain significance in LAMB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-09). AlphaMissense: likely benign (0.0984); Ultra-rare (popmax 0.0495%, mid); Associated with Inborn genetic diseases.

What condition is associated with LAMB3 p.Pro425Leu (c.1274C>T)?

LAMB3 p.Pro425Leu (c.1274C>T) is associated with Inborn genetic diseases (ClinVar).

How common is LAMB3 p.Pro425Leu (c.1274C>T) in the general population?

LAMB3 p.Pro425Leu (c.1274C>T) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about LAMB3 p.Pro425Leu (c.1274C>T)?

AlphaMissense predicts likely benign (score 0.0984) — an in-silico prediction, not a clinical call.

LAMB3 p.Pro425Leu

c.1274C>T · rs150917125 · VCV3117609

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0984 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0984	likely benign
REVEL	0.485	indeterminate
SaProt	LLR -9.17	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 36 kb · p 0.27 · regional, not allelic
Overall
CADD	27.4	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 0.0495% Middle Eastern · 3/6,066 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00802%

Overall 0.00579% 93/1,605,772 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,022
Admixed American	0.0185%	5,400
Remaining individualsnot grpmax-eligible	0.0129%	7,760
East Asian	0.00673%	14,850
European (non-Finnish)	0.00544%	18,376
African / African-American	0.00268%	37,364
South Asian	0.00224%	44,735

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.Pro425Leu
Coding: c.1274C>T
MANE Select: NM_000228
dbSNP: rs150917125
Type: single nucleotide variant
Location: chr1:209628049 (GRCh38)
Gene constraint: LOEUF 0.829 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.55
Residue 425: a disulfide bond; the laminin egf-like 3 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.Pro425= Likely benign ★ same residue
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

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-pro425leu (accessed [today's date]).

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