Is LEMD3 p.Phe516Val (c.1546T>G) pathogenic?

LEMD3 p.Phe516Val (c.1546T>G) is classified Uncertain significance in LEMD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely benign (0.2177); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with LEMD3 p.Phe516Val (c.1546T>G)?

LEMD3 p.Phe516Val (c.1546T>G) is associated with Inborn genetic diseases (ClinVar).

How common is LEMD3 p.Phe516Val (c.1546T>G) in the general population?

LEMD3 p.Phe516Val (c.1546T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LEMD3 p.Phe516Val (c.1546T>G)?

AlphaMissense predicts likely benign (score 0.2177) — an in-silico prediction, not a clinical call.

LEMD3 p.Phe516Val

c.1546T>G · VCV4623591

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2177 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2177	likely benign
REVEL	0.097	moderately benign-leaning
SaProt	LLR -6.08	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 75 kb · p 5.1e-06 · regional, not allelic
Overall
CADD	24.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: LEMD3
Protein: p.Phe516Val
Coding: c.1546T>G
MANE Select: NM_014319
Type: single nucleotide variant
Location: chr12:65210949 (GRCh38)
Gene constraint: LOEUF 0.584 · pLI 0.40 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.07 · 3 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LEMD3 p.Phe516Ser Uncertain significance ★ ⚠ same residue
LEMD3 p.Arg537Ter Pathogenic ★★ same condition
LEMD3 p.Ala163Pro Uncertain significance ★★ ⚠ same condition
LEMD3 p.Ala179Asp Uncertain significance ★★ ⚠ same condition
LEMD3 p.Ala338Val Uncertain significance ★★ ⚠ same condition
LEMD3 p.Ala415Val Uncertain significance ★★ ⚠ same condition
LEMD3 p.Ala417Val Uncertain significance ★★ ⚠ same condition
LEMD3 p.Ala5Pro 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-phe516val (accessed [today's date]).

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