Is LEMD3 p.Pro37Arg (c.110C>G) pathogenic?

LEMD3 p.Pro37Arg (c.110C>G) is classified Uncertain significance in LEMD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-20). AlphaMissense: likely pathogenic (0.9602); Very rare (popmax 0.0023%, sas).

How common is LEMD3 p.Pro37Arg (c.110C>G) in the general population?

LEMD3 p.Pro37Arg (c.110C>G) is very rare (popmax 0.0023%, sas) (gnomAD).

What do computational predictors say about LEMD3 p.Pro37Arg (c.110C>G)?

AlphaMissense predicts likely pathogenic (score 0.9602) — an in-silico prediction, not a clinical call.

LEMD3 p.Pro37Arg

c.110C>G · rs766098043 · VCV3010064

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9602 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0023%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9602	likely pathogenic
REVEL	0.286	benign-leaning
SaProt	LLR -3.92	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
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 1.20	unconstrained · MANE · 1,339 bp · p 4.4e-07 · regional, not allelic
Overall
CADD	25.6	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 0.0023% South Asian · 2/87,112 alleles

Filtering AF 0.000381% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000213%

Overall 0.000694% 11/1,584,918 alleles · very rare exomes 11/1,432,578 · genomes 0/152,340 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0023%	43,556
Remaining individualsnot grpmax-eligible	0.00163%	61,416
European (non-Finnish)	0.000686%	145,752

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.Pro37Arg
Coding: c.110C>G
MANE Select: NM_014319
dbSNP: rs766098043
Type: single nucleotide variant
Location: chr12:65169706 (GRCh38)
Gene constraint: LOEUF 0.584 · pLI 0.40 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.07 · 3 PDB
Residue 37: the lem domain; the 'disordered' region

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

Similar variants

LEMD3 p.Pro37= 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
LEMD3 p.Tyr441Ter 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-pro37arg (accessed [today's date]).

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