Is SPEG p.Pro2102Ser (c.6304C>T) pathogenic?

SPEG p.Pro2102Ser (c.6304C>T) is classified Uncertain significance in SPEG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-24). AlphaMissense: likely benign (0.3316); Rare (popmax 0.107%, eas); Associated with myopathy, centronuclear, 5.

What condition is associated with SPEG p.Pro2102Ser (c.6304C>T)?

SPEG p.Pro2102Ser (c.6304C>T) is associated with myopathy, centronuclear, 5 (ClinVar).

How common is SPEG p.Pro2102Ser (c.6304C>T) in the general population?

SPEG p.Pro2102Ser (c.6304C>T) is rare (popmax 0.107%, eas) (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.Pro2102Ser (c.6304C>T)?

AlphaMissense predicts likely benign (score 0.3316) — an in-silico prediction, not a clinical call.

SPEG p.Pro2102Ser

c.6304C>T · rs766934083 · VCV1934617

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3316 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.107%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

myopathy, centronuclear, 5

Computational evidence

Protein change
AlphaMissense	0.3316	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 4.8	GERP 1.1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 7,108 bp · p 0.064 · regional, not allelic
Overall
CADD	18.82	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

Grpmax group 0.107% East Asian · 45/41,960 alleles

Filtering AF 0.0823% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0735%

Overall 0.00671% 104/1,550,372 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.107%	932
Finnishnot grpmax-eligible	0.0462%	2,165
Remaining individualsnot grpmax-eligible	0.00827%	12,093
European (non-Finnish)	0.00277%	36,102
South Asian	0.00117%	85,576

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: SPEG
Protein: p.Pro2102Ser
Coding: c.6304C>T
MANE Select: NM_005876
dbSNP: rs766934083
Type: single nucleotide variant
Location: chr2:219483767 (GRCh38)

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

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-pro2102ser (accessed [today's date]).

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