Is ANO5 p.Ser537Pro (c.1609T>C) pathogenic?

ANO5 p.Ser537Pro (c.1609T>C) is classified Uncertain significance in ANO5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-02). AlphaMissense: likely pathogenic (0.9225); Very rare (popmax 0.00167%, amr); Associated with autosomal recessive limb-girdle muscular dystrophy type 2L.

How common is ANO5 p.Ser537Pro (c.1609T>C) in the general population?

ANO5 p.Ser537Pro (c.1609T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ANO5 p.Ser537Pro (c.1609T>C)?

AlphaMissense predicts likely pathogenic (score 0.9225) — an in-silico prediction, not a clinical call.

ANO5 p.Ser537Pro

Q: What condition is associated with ANO5 p.Ser537Pro (c.1609T>C)?

ANO5 p.Ser537Pro (c.1609T>C) is associated with autosomal recessive limb-girdle muscular dystrophy type 2L, gnathodiaphyseal dysplasia (ClinVar).

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.1609T>C · rs773518330 · VCV1052251

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9225 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2L

Computational evidence

Protein change
AlphaMissense	0.9225	likely pathogenic
REVEL	0.375	indeterminate
SaProt	LLR -13.27	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.3	GERP 1.2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 86 kb · p 0.66 · regional, not allelic
Overall
CADD	24.8	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,976 alleles

Overall 0.000124% 2/1,613,356 alleles · very rare exomes 1/1,461,166 · genomes 1/152,190 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,976
African / African-American	0.00133%	74,938

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.Ser537Pro
Coding: c.1609T>C
MANE Select: NM_213599
dbSNP: rs773518330
Type: single nucleotide variant
Location: chr11:22259720 (GRCh38)
Gene constraint: LOEUF 1.034 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.22
Residue 537: a UniProt-annotated variant site (in lgmdr12)

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

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

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood

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-ser537pro (accessed [today's date]).

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