Is ANK3 p.Val3228Leu (c.9682G>C) pathogenic?

ANK3 p.Val3228Leu (c.9682G>C) is classified Benign in ANK3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.0754); Low-frequency (popmax 4.14%, afr).

How common is ANK3 p.Val3228Leu (c.9682G>C) in the general population?

ANK3 p.Val3228Leu (c.9682G>C) is low-frequency (popmax 4.14%, afr) (gnomAD).

What do computational predictors say about ANK3 p.Val3228Leu (c.9682G>C)?

AlphaMissense predicts likely benign (score 0.0754) — an in-silico prediction, not a clinical call.

ANK3 p.Val3228Leu

c.9682G>C · rs61732399 · VCV780863

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0754 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.14%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.0754	likely benign
REVEL	0.023	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.93	GERP -0.65
Regional constraint	o/e 0.92	unconstrained · MANE · 4,360 bp · p 0.0017 · regional, not allelic
Overall
CADD	2.776	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 4.14% African / African-American · 3,106/75,024 alleles

Filtering AF 4.02% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.97%

Overall 0.221% 3,574/1,614,142 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.14%	24
Remaining individualsnot grpmax-eligible	0.307%	326
Admixed American	0.267%	375
Middle Eastern	0.231%	433
South Asian	0.00988%	10,121
European (non-Finnish)	0.00788%	12,688

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.Val3228Leu
Coding: c.9682G>C
MANE Select: NM_020987
dbSNP: rs61732399
Type: single nucleotide variant
Location: chr10:60071199 (GRCh38)
Gene constraint: LOEUF 0.16 · pLI 1.00 (gnomAD)
Residue 3228: the 'disordered' region

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

Similar variants

ANK3 p.Val3228Ile Uncertain significance ★ ⚠ same residue
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

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-val3228leu (accessed [today's date]).

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