Is LEMD3 p.Pro449Ser (c.1345C>T) pathogenic?

LEMD3 p.Pro449Ser (c.1345C>T) is classified Uncertain significance in LEMD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-08). AlphaMissense: ambiguous (0.4133); Very rare (popmax 0.000424%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LEMD3 p.Pro449Ser (c.1345C>T)?

LEMD3 p.Pro449Ser (c.1345C>T) is associated with Inborn genetic diseases (ClinVar).

How common is LEMD3 p.Pro449Ser (c.1345C>T) in the general population?

LEMD3 p.Pro449Ser (c.1345C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about LEMD3 p.Pro449Ser (c.1345C>T)?

AlphaMissense predicts ambiguous (score 0.4133) — an in-silico prediction, not a clinical call.

LEMD3 p.Pro449Ser

c.1345C>T · rs371748000 · VCV2899834

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4133 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4133	ambiguous
REVEL	0.407	indeterminate
SaProt	LLR -3.88	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 75 kb · p 5.1e-06 · regional, not allelic
Overall
CADD	24.7	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 0.000424% European (non-Finnish) · 5/1,180,056 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,614,090 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: LEMD3
Protein: p.Pro449Ser
Coding: c.1345C>T
MANE Select: NM_014319
dbSNP: rs371748000
Type: single nucleotide variant
Location: chr12:65170941 (GRCh38)
Gene constraint: LOEUF 0.584 · pLI 0.40 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.07 · 3 PDB

Full LEMD3 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

LEMD3 p.Arg537Ter Pathogenic ★★ same condition
LEMD3 p.Ala163Pro Uncertain significance ★★ ⚠ same condition
LEMD3 p.Ala179Asp Uncertain significance ★★ ⚠ same condition
LEMD3 p.Ala338Val Uncertain significance ★★ ⚠ same condition
LEMD3 p.Ala415Val Uncertain significance ★★ ⚠ same condition
LEMD3 p.Ala417Val Uncertain significance ★★ ⚠ same condition
LEMD3 p.Ala5Pro Uncertain significance ★★ ⚠ same condition
LEMD3 p.Ala5Thr 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/lemd3-p-pro449ser (accessed [today's date]).

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