Is ANO4 p.Thr259Ser (c.775A>T) pathogenic?

ANO4 p.Thr259Ser (c.775A>T) is classified Uncertain significance in ANO4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). AlphaMissense: likely benign (0.2811); Very rare (popmax 0.00133%, afr).

How common is ANO4 p.Thr259Ser (c.775A>T) in the general population?

ANO4 p.Thr259Ser (c.775A>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ANO4 p.Thr259Ser (c.775A>T)?

AlphaMissense predicts likely benign (score 0.2811) — an in-silico prediction, not a clinical call.

ANO4 p.Thr259Ser

c.775A>T · rs761645448 · VCV3127099

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2811 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2811	likely benign
REVEL	0.293	indeterminate
SaProt	LLR -10.59	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 139 kb · p 1.7e-19 · regional, not allelic
Overall
CADD	25.3	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 0.00133% African / African-American · 1/74,914 alleles

Overall 0.000657% 1/152,240 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: ANO4
Protein: p.Thr259Ser
Coding: c.775A>T
MANE Select: NM_001286615
dbSNP: rs761645448
Type: single nucleotide variant
Location: chr12:101020074 (GRCh38)
Gene constraint: LOEUF 0.576 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.27

Full ANO4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANO4 p.Thr259Ala Uncertain significance ★ ⚠ same residue
ANO4 p.Thr259Arg Uncertain significance ★ ⚠ same residue
ANO4 p.Phe720Leu Uncertain significance ★★ ⚠ same type
ANO4 p.Val376Ile Likely benign ★★ same type
ANO4 p.Asn129Lys Pathogenic ★ ⚠ same type
ANO4 p.Asn558Lys Pathogenic ★ same type
ANO4 p.Asn603Asp Pathogenic ★ same type
ANO4 p.Ile562Phe Pathogenic ★ same type

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/ano4-p-thr259ser (accessed [today's date]).

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