Is SPEG p.Pro86Arg (c.257C>G) pathogenic?

SPEG p.Pro86Arg (c.257C>G) is classified Uncertain significance in SPEG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-02-28). AlphaMissense: likely benign (0.2127); Absent from gnomAD v4.1; Associated with myopathy, centronuclear, 5.

What condition is associated with SPEG p.Pro86Arg (c.257C>G)?

SPEG p.Pro86Arg (c.257C>G) is associated with myopathy, centronuclear, 5 (ClinVar).

How common is SPEG p.Pro86Arg (c.257C>G) in the general population?

SPEG p.Pro86Arg (c.257C>G) is absent from gnomAD v4.1 (gnomAD).

How is Autosomal recessive centronuclear myopathy inherited?

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

What do computational predictors say about SPEG p.Pro86Arg (c.257C>G)?

AlphaMissense predicts likely benign (score 0.2127) — an in-silico prediction, not a clinical call.

SPEG p.Pro86Arg

c.257C>G · rs1365650391 · VCV2436288

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2127 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

myopathy, centronuclear, 5

Computational evidence

Protein change
AlphaMissense	0.2127	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 1.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 27 kb · p 0.32 · regional, not allelic
Overall
CADD	20.9	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 is an independent agreement signal.

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: SPEG
Protein: p.Pro86Arg
Coding: c.257C>G
MANE Select: NM_005876
dbSNP: rs1365650391
Type: single nucleotide variant
Location: chr2:219435234 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI <0.01 (gnomAD)
Residue 86: the ig-like 1 domain

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

Disease context

myopathy, centronuclear, 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive centronuclear myopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

SPEG p.Pro86= Likely benign ★ same residue
SPEG p.Ala154Asp Uncertain significance ★★ ⚠ same condition
SPEG p.Ala1628Val Uncertain significance ★★ same condition
SPEG p.Ala259Thr Uncertain significance ★★ ⚠ same condition
SPEG p.Ala267Glu Uncertain significance ★★ ⚠ same condition
SPEG p.Arg1004Cys Uncertain significance ★★ same condition
SPEG p.Arg1059Trp Uncertain significance ★★ same condition
SPEG p.Arg114Trp 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/speg-p-pro86arg (accessed [today's date]).

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