Is ANO3 p.Pro776Ser (c.2326C>T) pathogenic?

ANO3 p.Pro776Ser (c.2326C>T) is classified Uncertain significance in ANO3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-14). AlphaMissense: likely pathogenic (0.9946); Very rare (popmax 0.000254%, nfe).

How common is ANO3 p.Pro776Ser (c.2326C>T) in the general population?

ANO3 p.Pro776Ser (c.2326C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about ANO3 p.Pro776Ser (c.2326C>T)?

AlphaMissense predicts likely pathogenic (score 0.9946) — an in-silico prediction, not a clinical call.

ANO3 p.Pro776Ser

c.2326C>T · VCV3359954

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9946 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9946	likely pathogenic · top 7% in ANO3
REVEL	0.812	moderately pathogenic-leaning
SaProt	LLR -13.85	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 1.9, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 129 kb · p 7.8e-20 · regional, not allelic
Overall
CADD	28.0	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

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,930 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,850 alleles · very rare exomes 2/1,461,728 · genomes 1/152,122 · joint denominator

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: ANO3
Protein: p.Pro776Ser
Coding: c.2326C>T
MANE Select: NM_031418
Type: single nucleotide variant
Location: chr11:26643232 (GRCh38)
Gene constraint: LOEUF 0.911 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.30

Full ANO3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANO3 p.Pro776= Likely benign ★ same residue
ANO3 p.Ala657Thr Likely pathogenic ★★ same type
ANO3 p.Asn648Ser Pathogenic/Likely pathogenic ★★ same type
ANO3 p.Glu510Lys Pathogenic/Likely pathogenic ★★ same type
ANO3 p.Gly567Arg Likely pathogenic ★★ same type
ANO3 p.Ile607Phe Pathogenic/Likely pathogenic ★★ same type
ANO3 c.1836+4A>C Uncertain significance ★★ same type
ANO3 c.2141+1G>A Uncertain significance ★★ 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/ano3-p-pro776ser (accessed [today's date]).

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