Is ANO5 p.Thr752= (c.2256G>A) pathogenic?

ANO5 p.Thr752= (c.2256G>A) is classified Conflicting classifications of pathogenicity in ANO5 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-06-01). Low-frequency (popmax 1.14%, sas); Associated with autosomal recessive limb-girdle muscular dystrophy type 2L.

What condition is associated with ANO5 p.Thr752= (c.2256G>A)?

ANO5 p.Thr752= (c.2256G>A) is associated with autosomal recessive limb-girdle muscular dystrophy type 2L, gnathodiaphyseal dysplasia, Miyoshi muscular dystrophy 3 (ClinVar).

How common is ANO5 p.Thr752= (c.2256G>A) in the general population?

ANO5 p.Thr752= (c.2256G>A) is low-frequency (popmax 1.14%, sas) (gnomAD).

ANO5 p.Thr752=

Q: How is Anoctamin-5-related limb-girdle muscular dystrophy R12 inherited?

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

c.2256G>A · rs144048656 · VCV285552

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.14%, sas)

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2L

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.71	GERP -5.5
Overall
CADD	6.016	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.14% South Asian · 1,018/89,610 alleles

Filtering AF 1.08% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.05%

Overall 0.101% 1,610/1,597,938 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	1.14%	88
Middle Eastern	0.55%	182
Remaining individualsnot grpmax-eligible	0.116%	859
European (non-Finnish)	0.04%	2,500
Admixed American	0.0236%	4,235
East Asian	0.0045%	22,202
Ashkenazi Jewishnot grpmax-eligible	0.00342%	29,234
African / African-American	0.0027%	37,069

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: ANO5
Protein: p.Thr752=
Coding: c.2256G>A
MANE Select: NM_213599
dbSNP: rs144048656
Type: single nucleotide variant
Location: chr11:22274589 (GRCh38)
Gene constraint: LOEUF 1.034 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.22
Residue 752: a UniProt-annotated variant site (in lgmdr12); a UniProt-annotated variant site (in lgmdr12; uncertain significance)

Full ANO5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: gnathodiaphyseal dysplasia Miyoshi muscular dystrophy 3

For Anoctamin-5-related limb-girdle muscular dystrophy R12 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood

Similar variants

ANO5 p.Thr752Met Uncertain significance ★ ⚠ same residue
ANO5 c.1898+1G>A Pathogenic ★★★ same condition
ANO5 c.41-1G>A Pathogenic ★★★ same condition
ANO5 p.Ala432Gly Pathogenic ★★★ ⚠ same condition
ANO5 p.Arg484Cys Likely pathogenic ★★★ same condition
ANO5 p.Arg50Ter Pathogenic ★★★ same condition
ANO5 p.Arg58Trp Pathogenic ★★★ ⚠ same condition
ANO5 p.Arg758Cys 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/ano5-p-thr752 (accessed [today's date]).

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