Is ANO5 p.Ser753= (c.2259A>G) pathogenic?

ANO5 p.Ser753= (c.2259A>G) is classified Benign in ANO5 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-03). Common (popmax 6%, afr) — too common for a highly-penetrant pathogenic allele; Associated with gnathodiaphyseal dysplasia.

What condition is associated with ANO5 p.Ser753= (c.2259A>G)?

ANO5 p.Ser753= (c.2259A>G) is associated with gnathodiaphyseal dysplasia, autosomal recessive limb-girdle muscular dystrophy type 2L (ClinVar).

ANO5 p.Ser753=

Q: How common is ANO5 p.Ser753= (c.2259A>G) in the general population?

ANO5 p.Ser753= (c.2259A>G) is common (popmax 6%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2259A>G · rs61746201 · VCV128389

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 6%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

gnathodiaphyseal dysplasia

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 -4.7	GERP -5.5
Overall
CADD	0.265	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6% African / African-American · 4,479/74,700 alleles

Filtering AF 5.85% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.79%

Overall 0.314% 5,038/1,604,686 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6%	17
Remaining individualsnot grpmax-eligible	0.404%	248
Admixed American	0.374%	268
Middle Eastern	0.166%	602
South Asian	0.0121%	8,233
European (non-Finnish)	0.00546%	18,332

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.Ser753=
Coding: c.2259A>G
MANE Select: NM_213599
dbSNP: rs61746201
Type: single nucleotide variant
Location: chr11:22274592 (GRCh38)
Gene constraint: LOEUF 1.034 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.22
Residue 753: 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

gnathodiaphyseal dysplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2L

Similar variants

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
ANO5 p.Asp81Gly 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-ser753 (accessed [today's date]).

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