Is LEMD3 p.Ser126= (c.378C>T) pathogenic?

LEMD3 p.Ser126= (c.378C>T) is classified Benign in LEMD3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-02). Common (popmax 18.6%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Buschke-Ollendorff syndrome.

What condition is associated with LEMD3 p.Ser126= (c.378C>T)?

LEMD3 p.Ser126= (c.378C>T) is associated with Buschke-Ollendorff syndrome (ClinVar).

LEMD3 p.Ser126=

Q: How common is LEMD3 p.Ser126= (c.378C>T) in the general population?

LEMD3 p.Ser126= (c.378C>T) is common (popmax 18.6%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.378C>T · rs61736593 · VCV310222

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 18.6%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

Buschke-Ollendorff syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.83	GERP -2.1
Overall
CADD	6.742	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 18.6% East Asian · 7,056/37,860 alleles

Filtering AF 18.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 18.1%

Overall 0.867% 12,690/1,464,352 alleles · common exomes 10,384/1,312,222 · genomes 2,306/152,130 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	18.6%	5
Admixed American	2.04%	49
South Asian	1.86%	54
Finnishnot grpmax-eligible	1.85%	54
Ashkenazi Jewishnot grpmax-eligible	1.83%	55
African / African-American	1.44%	69
Remaining individualsnot grpmax-eligible	1.26%	79
Middle Eastern	0.227%	440
European (non-Finnish)	0.0521%	1,920

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.Ser126=
Coding: c.378C>T
MANE Select: NM_014319
dbSNP: rs61736593
Type: single nucleotide variant
Location: chr12:65169974 (GRCh38)
Gene constraint: LOEUF 0.584 · pLI 0.40 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.07 · 3 PDB
Residue 126: 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-ser126 (accessed [today's date]).

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