Is ANO5 p.Pro666fs (c.1993_1996dup) pathogenic?

ANO5 p.Pro666fs (c.19931996dup) is classified Pathogenic in ANO5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-16). Very rare (popmax 0.000339%, nfe); Associated with gnathodiaphyseal dysplasia.

What condition is associated with ANO5 p.Pro666fs (c.1993_1996dup)?

ANO5 p.Pro666fs (c.1993_1996dup) is associated with gnathodiaphyseal dysplasia, autosomal recessive limb-girdle muscular dystrophy type 2L (ClinVar).

How common is ANO5 p.Pro666fs (c.1993_1996dup) in the general population?

ANO5 p.Pro666fs (c.1993_1996dup) is very rare (popmax 0.000339%, nfe) (gnomAD).

ANO5 p.Pro666fs

c.1993_1996dup · rs780201679 · VCV871508

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

gnathodiaphyseal dysplasia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 18 of 22
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.99	GERP -3.9, phastCons 0.006
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,020 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,082 alleles · very rare

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.Pro666fs
Coding: c.1993_1996dup
MANE Select: NM_213599
dbSNP: rs780201679
Type: Duplication
Location: chr11:22270405 (GRCh38)
Gene constraint: LOEUF 1.034 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.22
Residue 666: 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 p.Asn64fs Pathogenic ★★★ same condition
ANO5 p.Leu330fs Pathogenic ★★★ same condition
ANO5 c.2236-2_2238dup Pathogenic/Likely pathogenic ★★ same condition
ANO5 p.Ile300fs Pathogenic ★★ same condition
ANO5 p.Met543fs Pathogenic ★★ same condition
ANO5 p.Ser726fs Pathogenic ★★ same condition
ANO5 p.Thr678fs Pathogenic/Likely pathogenic ★★ same condition
ANO5 c.1631-11dup Benign/Likely benign ★★ 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-pro666fs (accessed [today's date]).

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