Is LEMD3 p.Arg901Pro (c.2702G>C) pathogenic?

LEMD3 p.Arg901Pro (c.2702G>C) is classified Uncertain significance in LEMD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: ambiguous (0.3961); Very rare (popmax 8.48e-05%, nfe).

How common is LEMD3 p.Arg901Pro (c.2702G>C) in the general population?

LEMD3 p.Arg901Pro (c.2702G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about LEMD3 p.Arg901Pro (c.2702G>C)?

AlphaMissense predicts ambiguous (score 0.3961) — an in-silico prediction, not a clinical call.

LEMD3 p.Arg901Pro

c.2702G>C · VCV4773345

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3961 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3961	ambiguous
REVEL	0.164	moderately benign-leaning
SaProt	LLR -5.57	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 75 kb · p 5.1e-06 · regional, not allelic
Overall
CADD	24.0	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 8.48e-05% European (non-Finnish) · 1/1,179,712 alleles

Overall 6.2e-05% 1/1,613,466 alleles · very rare exomes 1/1,461,316 · genomes 0/152,150 · joint denominator

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.Arg901Pro
Coding: c.2702G>C
MANE Select: NM_014319
Type: single nucleotide variant
Location: chr12:65246291 (GRCh38)
Gene constraint: LOEUF 0.584 · pLI 0.40 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.07 · 3 PDB
Residue 901: the 'interaction with smad1, smad2, smad3 and smad5' region; the 'disordered' region; a UniProt-annotated variant site (in bos; patient does not show osteopoikilosis); a UniProt-annotated variant site (in bos)

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

Similar variants

LEMD3 p.Arg901Gln Uncertain significance ★ ⚠ same residue
LEMD3 p.Arg901Trp 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-arg901pro (accessed [today's date]).

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