Is LEMD3 p.Gly343Arg (c.1027G>A) pathogenic?

LEMD3 p.Gly343Arg (c.1027G>A) is classified Uncertain significance in LEMD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely benign (0.1329); Very rare (popmax 0.00446%, eas); Associated with Buschke-Ollendorff syndrome.

What condition is associated with LEMD3 p.Gly343Arg (c.1027G>A)?

LEMD3 p.Gly343Arg (c.1027G>A) is associated with Buschke-Ollendorff syndrome (ClinVar).

How common is LEMD3 p.Gly343Arg (c.1027G>A) in the general population?

LEMD3 p.Gly343Arg (c.1027G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about LEMD3 p.Gly343Arg (c.1027G>A)?

AlphaMissense predicts likely benign (score 0.1329) — an in-silico prediction, not a clinical call.

LEMD3 p.Gly343Arg

c.1027G>A · rs886049777 · VCV310230

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1329 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Buschke-Ollendorff syndrome

Computational evidence

Protein change
AlphaMissense	0.1329	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -6.16	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 9.4	GERP -0.4, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 1,339 bp · p 4.4e-07 · regional, not allelic
Overall
CADD	22.1	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 0.00446% East Asian · 2/44,870 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000137% 2/1,461,870 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.Gly343Arg
Coding: c.1027G>A
MANE Select: NM_014319
dbSNP: rs886049777
Type: single nucleotide variant
Location: chr12:65170623 (GRCh38)
Gene constraint: LOEUF 0.584 · pLI 0.40 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.07 · 3 PDB
Residue 343: the 'disordered' region

Full LEMD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Buschke-Ollendorff syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LEMD3 p.Arg678Ter Pathogenic/Likely pathogenic ★★ same condition
LEMD3 p.Glu601Ter Pathogenic/Likely pathogenic ★★ same condition
LEMD3 p.Ala127Val Uncertain significance ★★ ⚠ same condition
LEMD3 p.Asn257Asp Uncertain significance ★★ ⚠ same condition
LEMD3 p.Asn529Ser Uncertain significance ★★ ⚠ same condition
LEMD3 p.Asp214Tyr Uncertain significance ★★ ⚠ same condition
LEMD3 p.Asp544Ala Uncertain significance ★★ ⚠ same condition
LEMD3 p.Asp755Asn 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-gly343arg (accessed [today's date]).

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