Is LMOD3 p.Arg486Trp (c.1456C>T) pathogenic?

LMOD3 p.Arg486Trp (c.1456C>T) is classified Uncertain significance in LMOD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-05-15). AlphaMissense: likely benign (0.1515); Very rare (popmax 0.00223%, eas); Associated with nemaline myopathy 10.

What condition is associated with LMOD3 p.Arg486Trp (c.1456C>T)?

LMOD3 p.Arg486Trp (c.1456C>T) is associated with nemaline myopathy 10 (ClinVar).

How common is LMOD3 p.Arg486Trp (c.1456C>T) in the general population?

LMOD3 p.Arg486Trp (c.1456C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Severe congenital nemaline myopathy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about LMOD3 p.Arg486Trp (c.1456C>T)?

AlphaMissense predicts likely benign (score 0.1515) — an in-silico prediction, not a clinical call.

LMOD3 p.Arg486Trp

c.1456C>T · rs769492984 · VCV1051306

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1515 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nemaline myopathy 10

Computational evidence

Protein change
AlphaMissense	0.1515	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -9.98	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 4.5	GERP -0.24, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 13 kb · p 0.0038 · regional, not allelic
Overall
CADD	24.2	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 0.00223% East Asian · 1/44,806 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,611,476 alleles · very rare exomes 5/1,461,594 · genomes 0/149,882 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,806
European (non-Finnish)	0.000339%	294,846

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: LMOD3
Protein: p.Arg486Trp
Coding: c.1456C>T
MANE Select: NM_198271
dbSNP: rs769492984
Type: single nucleotide variant
Location: chr3:69118899 (GRCh38)
Gene constraint: LOEUF 0.948 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.79

Full LMOD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nemaline myopathy 10 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Severe congenital nemaline myopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

LMOD3 p.Arg486Gly Uncertain significance ★★ ⚠ same residue
LMOD3 p.Arg486= Likely benign ★ same residue
LMOD3 p.Arg486Leu Uncertain significance ★ ⚠ same residue
LMOD3 p.Gln36Ter Pathogenic ★★ same condition
LMOD3 p.Leu550Phe Pathogenic ★★ ⚠ same condition
LMOD3 p.Ala299Thr Uncertain significance ★★ ⚠ same condition
LMOD3 p.Ala475Thr Uncertain significance ★★ ⚠ same condition
LMOD3 p.Ala502Gly 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/lmod3-p-arg486trp (accessed [today's date]).

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