Is LEMD3 p.Ala85Pro (c.253G>C) pathogenic?

LEMD3 p.Ala85Pro (c.253G>C) is classified Uncertain significance in LEMD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-09). AlphaMissense: likely benign (0.0976); Very rare (popmax 0.00163%, nfe).

How common is LEMD3 p.Ala85Pro (c.253G>C) in the general population?

LEMD3 p.Ala85Pro (c.253G>C) is very rare (popmax 0.00163%, nfe) (gnomAD).

What do computational predictors say about LEMD3 p.Ala85Pro (c.253G>C)?

AlphaMissense predicts likely benign (score 0.0976) — an in-silico prediction, not a clinical call.

LEMD3 p.Ala85Pro

c.253G>C · rs1411780418 · VCV1448807

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0976 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00163%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0976	likely benign
REVEL	0.122	moderately benign-leaning
SaProt	LLR -8.73	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 -0.1	GERP -0.1, phastCons 0.91
Regional constraint	o/e 1.20	unconstrained · MANE · 1,339 bp · p 4.4e-07 · regional, not allelic
Overall
CADD	13.98	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 0.00163% European (non-Finnish) · 18/1,102,280 alleles

Filtering AF 0.00102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000842%

Overall 0.00123% 18/1,458,960 alleles · very rare exomes 15/1,307,164 · genomes 3/151,796 · 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.Ala85Pro
Coding: c.253G>C
MANE Select: NM_014319
dbSNP: rs1411780418
Type: single nucleotide variant
Location: chr12:65169849 (GRCh38)
Gene constraint: LOEUF 0.584 · pLI 0.40 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.07 · 3 PDB
Residue 85: the 'disordered' region

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

Similar variants

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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
LEMD3 p.Ala127Val Uncertain significance ★★ ⚠ 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-ala85pro (accessed [today's date]).

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