Is LMOD3 p.Pro556Arg (c.1667C>G) pathogenic?

LMOD3 p.Pro556Arg (c.1667C>G) is classified Uncertain significance in LMOD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-25). AlphaMissense: likely pathogenic (0.6404); Absent from gnomAD v4.1; Associated with nemaline myopathy 10.

What condition is associated with LMOD3 p.Pro556Arg (c.1667C>G)?

LMOD3 p.Pro556Arg (c.1667C>G) is associated with nemaline myopathy 10 (ClinVar).

How common is LMOD3 p.Pro556Arg (c.1667C>G) in the general population?

LMOD3 p.Pro556Arg (c.1667C>G) is absent from gnomAD v4.1 (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.Pro556Arg (c.1667C>G)?

AlphaMissense predicts likely pathogenic (score 0.6404) — an in-silico prediction, not a clinical call.

LMOD3 p.Pro556Arg

c.1667C>G · rs201205115 · VCV2010520

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6404 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

nemaline myopathy 10

Computational evidence

Protein change
AlphaMissense	0.6404	likely pathogenic
REVEL	0.302	indeterminate
SaProt	LLR -10.68	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 13 kb · p 0.0038 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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: LMOD3
Protein: p.Pro556Arg
Coding: c.1667C>G
MANE Select: NM_198271
dbSNP: rs201205115
Type: single nucleotide variant
Location: chr3:69109111 (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.Pro556Gln Conflicting classifications of pathogenicity ★ ⚠ 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
LMOD3 p.Ala548Thr Uncertain significance ★★ ⚠ same condition
LMOD3 p.Arg111Cys 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-pro556arg (accessed [today's date]).

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