Is SPEG p.Pro749Ser (c.2245C>T) pathogenic?

SPEG p.Pro749Ser (c.2245C>T) is classified Uncertain significance in SPEG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-06). AlphaMissense: likely pathogenic (0.6958); Ultra-rare (popmax 0.0167%, mid); Associated with myopathy, centronuclear, 5.

What condition is associated with SPEG p.Pro749Ser (c.2245C>T)?

SPEG p.Pro749Ser (c.2245C>T) is associated with myopathy, centronuclear, 5 (ClinVar).

How common is SPEG p.Pro749Ser (c.2245C>T) in the general population?

SPEG p.Pro749Ser (c.2245C>T) is ultra-rare (popmax 0.0167%, mid) (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.Pro749Ser (c.2245C>T)?

AlphaMissense predicts likely pathogenic (score 0.6958) — an in-silico prediction, not a clinical call.

SPEG p.Pro749Ser

c.2245C>T · rs1347181252 · VCV1913918

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6958 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

myopathy, centronuclear, 5

Computational evidence

Protein change
AlphaMissense	0.6958	likely pathogenic
REVEL	0.783	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 27 kb · p 0.32 · regional, not allelic
Overall
CADD	24.6	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Middle Eastern · 1/5,974 alleles

Filtering AF 0.000367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000373% 6/1,609,432 alleles · ultra-rare exomes 3/1,457,224 · genomes 3/152,208 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,974
Ashkenazi Jewishnot grpmax-eligible	0.00341%	29,296
South Asian	0.00221%	45,234
European (non-Finnish)	0.00017%	589,039

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.Pro749Ser
Coding: c.2245C>T
MANE Select: NM_005876
dbSNP: rs1347181252
Type: single nucleotide variant
Location: chr2:219451267 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI <0.01 (gnomAD)
Residue 749: the ig-like 2 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.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
SPEG p.Arg1433Gln 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-pro749ser (accessed [today's date]).

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