Is ANK3 p.Ala4098= (c.12294C>T) pathogenic?

ANK3 p.Ala4098= (c.12294C>T) is classified Conflicting classifications of pathogenicity in ANK3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-09-29). Very rare (popmax 0.00401%, afr).

How common is ANK3 p.Ala4098= (c.12294C>T) in the general population?

ANK3 p.Ala4098= (c.12294C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

ANK3 p.Ala4098=

c.12294C>T · rs138073935 · VCV2439085

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.028	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.013	GERP -2.8, phastCons 0.2
Overall
CADD	10.82	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,826 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00391% 63/1,609,624 alleles · very rare exomes 54/1,457,542 · genomes 9/152,082 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.129%	777
Remaining individualsnot grpmax-eligible	0.00963%	10,389
African / African-Americangrpmax	0.00401%	24,942
Admixed American	0.00334%	29,965
South Asian	0.00221%	45,258
European (non-Finnish)	0.00102%	98,071

Ashkenazi Jewish 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: ANK3
Protein: p.Ala4098=
Coding: c.12294C>T
MANE Select: NM_020987
dbSNP: rs138073935
Type: single nucleotide variant
Location: chr10:60067960 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Residue 4098: an α-helix; the death domain

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-ala4098 (accessed [today's date]).

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