Is ANO5 p.Pro251Ser (c.751C>T) pathogenic?

ANO5 p.Pro251Ser (c.751C>T) is classified Uncertain significance in ANO5 (ClinVar, Expert panel, 3 submitters; last evaluated 2026-03-13). AlphaMissense: likely pathogenic (0.5858); Absent from gnomAD v4.1; Associated with autosomal recessive limb-girdle muscular dystrophy.

What condition is associated with ANO5 p.Pro251Ser (c.751C>T)?

ANO5 p.Pro251Ser (c.751C>T) is associated with autosomal recessive limb-girdle muscular dystrophy, gnathodiaphyseal dysplasia, autosomal recessive limb-girdle muscular dystrophy type 2L (ClinVar).

How common is ANO5 p.Pro251Ser (c.751C>T) in the general population?

ANO5 p.Pro251Ser (c.751C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ANO5 p.Pro251Ser (c.751C>T)?

AlphaMissense predicts likely pathogenic (score 0.5858) — an in-silico prediction, not a clinical call.

ANO5 p.Pro251Ser

c.751C>T · rs2133648746 · VCV1488412

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5858 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy

ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP

Uncertain Significance for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):

PM3_Supporting PM2_Supporting PP3 PP4

Curation rationale (ClinGen, verbatim)

The NM_213599.3: c.751G>T variant in ANO5 is a missense variant expected to cause the substitution of proline with serine at position 251, p.(Pro251Ser). This variant has been reported in one individual with a clinical suspicion of LGMD, where it was identified in unconfirmed phase with a pathogenic variant (c.108_109del p.(Glu36AspfsTer7), 0.5 pts, PMID: 37688281) (PM3_Supporting, PP4). This variant is absent from gnomAD v4.1.0 in a region with good sequencing coverage (PM2_Supporting). The computational predictor REVEL gives a score of 0.75, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to ANO5 function (PP3). In summary, there is currently insufficient evidence to classify this variant as pathogenic or benign, and it remains a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 03/13/2026): PM3_Supporting, PP4, PM2_Supporting, PP3.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.5858	likely pathogenic
REVEL	0.75	pathogenic-leaning
SaProt	LLR -10.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 86 kb · p 0.66 · regional, not allelic
Overall
CADD	24.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ANO5
Protein: p.Pro251Ser
Coding: c.751C>T
MANE Select: NM_213599
dbSNP: rs2133648746
Type: single nucleotide variant
Location: chr11:22236265 (GRCh38)
Gene constraint: LOEUF 1.034 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.22

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

Disease context

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

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

Similar variants

ANO5 p.Pro251Gln Uncertain significance ★ ⚠ same residue
ANO5 p.Pro251Thr Uncertain significance ★ ⚠ same residue
ANO5 p.Pro251fs Pathogenic ★ 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

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-pro251ser (accessed [today's date]).

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