Is ANK3 p.Arg3719His (c.11156G>A) pathogenic?

ANK3 p.Arg3719His (c.11156G>A) is classified Uncertain significance in ANK3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-01). AlphaMissense: ambiguous (0.4349); Very rare (popmax 0.00407%, nfe).

How common is ANK3 p.Arg3719His (c.11156G>A) in the general population?

ANK3 p.Arg3719His (c.11156G>A) is very rare (popmax 0.00407%, nfe) (gnomAD).

What do computational predictors say about ANK3 p.Arg3719His (c.11156G>A)?

AlphaMissense predicts ambiguous (score 0.4349) — an in-silico prediction, not a clinical call.

ANK3 p.Arg3719His

c.11156G>A · VCV3612380

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4349 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00407%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4349	ambiguous
REVEL	0.202	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 5.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 1,310 bp · p 0.15 · regional, not allelic
Overall
CADD	26.4	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 0.00407% European (non-Finnish) · 48/1,179,884 alleles

Filtering AF 0.00315% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00366% 59/1,613,476 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.008%	12,493
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,793
European (non-Finnish)grpmax	0.00407%	24,581
Admixed American	0.00334%	29,947
South Asian	0.0022%	45,488

Remaining individuals 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.Arg3719His
Coding: c.11156G>A
MANE Select: NM_020987
Type: single nucleotide variant
Location: chr10:60069725 (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 p.Arg3719Cys Uncertain significance ★ ⚠ same residue
ANK3 p.Arg3719Leu 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

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-arg3719his (accessed [today's date]).

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