Is SPEG p.Pro18Ser (c.52C>T) pathogenic?

SPEG p.Pro18Ser (c.52C>T) is classified Uncertain significance in SPEG (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-04-05). AlphaMissense: likely benign (0.1308); Ultra-rare (popmax 0.0357%, nfe); Associated with myopathy, centronuclear, 5.

What condition is associated with SPEG p.Pro18Ser (c.52C>T)?

SPEG p.Pro18Ser (c.52C>T) is associated with myopathy, centronuclear, 5 (ClinVar).

How common is SPEG p.Pro18Ser (c.52C>T) in the general population?

SPEG p.Pro18Ser (c.52C>T) is ultra-rare (popmax 0.0357%, nfe) (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.Pro18Ser (c.52C>T)?

AlphaMissense predicts likely benign (score 0.1308) — an in-silico prediction, not a clinical call.

SPEG p.Pro18Ser

c.52C>T · rs544959269 · VCV1432832

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1308 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0357%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

myopathy, centronuclear, 5

Computational evidence

Protein change
AlphaMissense	0.1308	likely benign
REVEL	0.119	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 1.1	GERP -2.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 27 kb · p 0.32 · regional, not allelic
Overall
CADD	20.5	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 0.0357% European (non-Finnish) · 404/1,132,484 alleles

Filtering AF 0.0328% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0317%

Overall 0.0293% 440/1,500,184 alleles · ultra-rare exomes 406/1,347,976 · genomes 34/152,208 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0357%	2,803
Remaining individualsnot grpmax-eligible	0.0308%	3,242
Admixed American	0.0253%	3,947
African / African-American	0.00581%	17,225
East Asian	0.00282%	35,512
Finnishnot grpmax-eligible	0.00228%	43,764

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.Pro18Ser
Coding: c.52C>T
MANE Select: NM_005876
dbSNP: rs544959269
Type: single nucleotide variant
Location: chr2:219435029 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI <0.01 (gnomAD)
Residue 18: the 'disordered' region

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.Pro18= 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-pro18ser (accessed [today's date]).

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