Is ANK3 p.Pro766Ser (c.2296C>T) pathogenic?

ANK3 p.Pro766Ser (c.2296C>T) is classified Uncertain significance in ANK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: ambiguous (0.3998); Ultra-rare (popmax 0.0347%, afr).

How common is ANK3 p.Pro766Ser (c.2296C>T) in the general population?

ANK3 p.Pro766Ser (c.2296C>T) is ultra-rare (popmax 0.0347%, afr) (gnomAD).

What do computational predictors say about ANK3 p.Pro766Ser (c.2296C>T)?

AlphaMissense predicts ambiguous (score 0.3998) — an in-silico prediction, not a clinical call.

ANK3 p.Pro766Ser

c.2296C>T · rs374120694 · VCV2189858

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3998 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, afr)

Computational evidence

Protein change
AlphaMissense	0.3998	ambiguous
REVEL	0.772	pathogenic-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 105 kb · p 5.9e-15 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0347% African / African-American · 26/74,982 alleles

Filtering AF 0.0242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.00198% 32/1,613,036 alleles · ultra-rare exomes 11/1,460,872 · genomes 21/152,164 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0347%	2,884
Middle Eastern	0.0165%	6,058
Admixed American	0.00667%	14,999
Remaining individualsnot grpmax-eligible	0.0016%	62,468

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: ANK3
Protein: p.Pro766Ser
Coding: c.2296C>T
MANE Select: NM_020987
dbSNP: rs374120694
Type: single nucleotide variant
Location: chr10:60172986 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)

Full ANK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANK3 c.2382+6C>T Uncertain significance ★★ same type
ANK3 p.Ala1461Thr Uncertain significance ★★ ⚠ same type
ANK3 p.Ala1534Val Uncertain significance ★★ same type
ANK3 p.Ala1630Val Uncertain significance ★★ ⚠ same type
ANK3 p.Ala169Thr Uncertain significance ★★ same type
ANK3 p.Ala2023Thr Uncertain significance ★★ ⚠ same type
ANK3 p.Ala218Thr Uncertain significance ★★ same type
ANK3 p.Ala2223Thr 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/ank3-p-pro766ser (accessed [today's date]).

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