Is CAPN3 p.Ser552Arg (c.1656C>A) pathogenic?

CAPN3 p.Ser552Arg (c.1656C>A) is classified Uncertain significance in CAPN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-26). AlphaMissense: likely pathogenic (0.6744); Very rare (popmax 0.00333%, amr); Associated with autosomal recessive limb-girdle muscular dystrophy type 2A.

What condition is associated with CAPN3 p.Ser552Arg (c.1656C>A)?

CAPN3 p.Ser552Arg (c.1656C>A) is associated with autosomal recessive limb-girdle muscular dystrophy type 2A (ClinVar).

How common is CAPN3 p.Ser552Arg (c.1656C>A) in the general population?

CAPN3 p.Ser552Arg (c.1656C>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CAPN3 p.Ser552Arg (c.1656C>A)?

AlphaMissense predicts likely pathogenic (score 0.6744) — an in-silico prediction, not a clinical call.

CAPN3 p.Ser552Arg

Q: How is Calpain-3-related limb-girdle muscular dystrophy R1 inherited?

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

c.1656C>A · rs751666282 · VCV1937470

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6744 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2A

Computational evidence

Protein change
AlphaMissense	0.6744	likely pathogenic
REVEL	0.667	pathogenic-leaning
SaProt	LLR -8.57	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.71 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.58	GERP -3.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,032 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000205% 3/1,461,856 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,016
European (non-Finnish)	8.47e-05%	1,180,013

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: CAPN3
Protein: p.Ser552Arg
Coding: c.1656C>A
MANE Select: NM_000070
dbSNP: rs751666282
Type: single nucleotide variant
Location: chr15:42402913 (GRCh38)
Gene constraint: LOEUF 0.896 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 79.18 · 5 PDB
Residue 552: the 'domain iii' region

Full CAPN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive limb-girdle muscular dystrophy type 2A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Calpain-3-related limb-girdle muscular dystrophy R1 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CAPN3 p.Ser552= Uncertain significance ★★ same residue
CAPN3 p.Ser552fs Likely pathogenic ★ same residue
CAPN3 c.1115+5G>C Pathogenic ★★★ same condition
CAPN3 c.1194-2A>G Pathogenic ★★★ same condition
CAPN3 c.1194-9A>G Pathogenic ★★★ same condition
CAPN3 c.1746-20C>G Pathogenic ★★★ same condition
CAPN3 c.1993-1G>A Pathogenic ★★★ same condition
CAPN3 c.499-1G>A Pathogenic ★★★ 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/capn3-p-ser552arg (accessed [today's date]).

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