Is ANO5 p.Ser375= (c.1125C>T) pathogenic?

ANO5 p.Ser375= (c.1125C>T) is classified Likely benign in ANO5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-29). Ultra-rare (popmax 0.0187%, afr); Associated with gnathodiaphyseal dysplasia.

What condition is associated with ANO5 p.Ser375= (c.1125C>T)?

ANO5 p.Ser375= (c.1125C>T) is associated with gnathodiaphyseal dysplasia, autosomal recessive limb-girdle muscular dystrophy type 2L (ClinVar).

How common is ANO5 p.Ser375= (c.1125C>T) in the general population?

ANO5 p.Ser375= (c.1125C>T) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

ANO5 p.Ser375=

c.1125C>T · rs139458696 · VCV1623493

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

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 -1.8	GERP -2.9
Overall
CADD	4.683	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% African / African-American · 14/74,968 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00904%

Overall 0.00143% 23/1,612,268 alleles · ultra-rare exomes 13/1,460,180 · genomes 10/152,088 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,355
Remaining individualsnot grpmax-eligible	0.00801%	12,490
Admixed American	0.00667%	14,991

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.Ser375=
Coding: c.1125C>T
MANE Select: NM_213599
dbSNP: rs139458696
Type: single nucleotide variant
Location: chr11:22250956 (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

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-ser375 (accessed [today's date]).

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