Is ANO5 p.Phe879Ser (c.2636T>C) pathogenic?

ANO5 p.Phe879Ser (c.2636T>C) is classified Uncertain significance in ANO5 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-07). AlphaMissense: likely pathogenic (0.8697); Very rare (popmax 0.000424%, nfe); Associated with gnathodiaphyseal dysplasia.

What condition is associated with ANO5 p.Phe879Ser (c.2636T>C)?

ANO5 p.Phe879Ser (c.2636T>C) is associated with gnathodiaphyseal dysplasia, autosomal recessive limb-girdle muscular dystrophy type 2L (ClinVar).

How common is ANO5 p.Phe879Ser (c.2636T>C) in the general population?

ANO5 p.Phe879Ser (c.2636T>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about ANO5 p.Phe879Ser (c.2636T>C)?

AlphaMissense predicts likely pathogenic (score 0.8697) — an in-silico prediction, not a clinical call.

ANO5 p.Phe879Ser

c.2636T>C · rs1459697236 · VCV635046

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8697 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

gnathodiaphyseal dysplasia

Computational evidence

Protein change
AlphaMissense	0.8697	likely pathogenic
REVEL	0.229	benign-leaning
SaProt	LLR -4.70	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 1.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 86 kb · p 0.66 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,192 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,612,840 alleles · very rare exomes 6/1,460,946 · genomes 1/151,894 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,220
European (non-Finnish)grpmax	0.000424%	235,838

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe879Ser
Coding: c.2636T>C
MANE Select: NM_213599
dbSNP: rs1459697236
Type: single nucleotide variant
Location: chr11:22279659 (GRCh38)
Gene constraint: LOEUF 1.034 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.22
Residue 879: 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-phe879ser (accessed [today's date]).

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