Is LEMD3 p.Pro237Ser (c.709C>T) pathogenic?

LEMD3 p.Pro237Ser (c.709C>T) is classified Uncertain significance in LEMD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-21). AlphaMissense: likely benign (0.0833); Very rare (popmax 0.00369%, nfe).

How common is LEMD3 p.Pro237Ser (c.709C>T) in the general population?

LEMD3 p.Pro237Ser (c.709C>T) is very rare (popmax 0.00369%, nfe) (gnomAD).

What do computational predictors say about LEMD3 p.Pro237Ser (c.709C>T)?

AlphaMissense predicts likely benign (score 0.0833) — an in-silico prediction, not a clinical call.

LEMD3 p.Pro237Ser

c.709C>T · rs755095379 · VCV3014761

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0833 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00369%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0833	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -6.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 1,339 bp · p 4.4e-07 · regional, not allelic
Overall
CADD	20.7	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 0.00369% European (non-Finnish) · 43/1,166,436 alleles

Filtering AF 0.00278% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00247%

Overall 0.0029% 46/1,586,324 alleles · very rare exomes 43/1,434,184 · genomes 3/152,140 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00369%	27,126
Remaining individualsnot grpmax-eligible	0.00325%	30,732
African / African-American	0.00135%	74,176

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.Pro237Ser
Coding: c.709C>T
MANE Select: NM_014319
dbSNP: rs755095379
Type: single nucleotide variant
Location: chr12:65170305 (GRCh38)
Gene constraint: LOEUF 0.584 · pLI 0.40 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.07 · 3 PDB
Residue 237: the 'disordered' region

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

Similar variants

LEMD3 p.Pro237Leu Uncertain significance ★ ⚠ same residue
LEMD3 p.Pro237= Likely benign ★ same residue
LEMD3 p.Arg537Ter Pathogenic ★★ same type
LEMD3 p.Arg625Ter Pathogenic ★★ same type
LEMD3 p.Arg655Ter Pathogenic/Likely pathogenic ★★ same type
LEMD3 p.Arg678Ter Pathogenic/Likely pathogenic ★★ same type
LEMD3 p.Arg735Ter Pathogenic ★★ same type
LEMD3 p.Glu601Ter Pathogenic/Likely pathogenic ★★ same type

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-pro237ser (accessed [today's date]).

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