Is LEMD3 p.Ser385Phe (c.1154C>T) pathogenic?

LEMD3 p.Ser385Phe (c.1154C>T) is classified Uncertain significance in LEMD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-15). AlphaMissense: likely benign (0.1091); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with LEMD3 p.Ser385Phe (c.1154C>T)?

LEMD3 p.Ser385Phe (c.1154C>T) is associated with Inborn genetic diseases (ClinVar).

How common is LEMD3 p.Ser385Phe (c.1154C>T) in the general population?

LEMD3 p.Ser385Phe (c.1154C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about LEMD3 p.Ser385Phe (c.1154C>T)?

AlphaMissense predicts likely benign (score 0.1091) — an in-silico prediction, not a clinical call.

LEMD3 p.Ser385Phe

c.1154C>T · rs372588607 · VCV1021128

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1091 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1091	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -9.62	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 5.3	GERP 1.8, phastCons 0.99
Regional constraint	o/e 1.20	unconstrained · MANE · 1,339 bp · p 4.4e-07 · regional, not allelic
Overall
CADD	23.8	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00217% 35/1,614,084 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.01%	10,002
Remaining individualsnot grpmax-eligible	0.008%	12,497
Finnishnot grpmax-eligible	0.00781%	12,809
European (non-Finnish)	0.00153%	65,557

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.Ser385Phe
Coding: c.1154C>T
MANE Select: NM_014319
dbSNP: rs372588607
Type: single nucleotide variant
Location: chr12:65170750 (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.Ser385Cys 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-ser385phe (accessed [today's date]).

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