Is ANKS3 p.Phe411Ser (c.1232T>C) pathogenic?

ANKS3 p.Phe411Ser (c.1232T>C) is classified Uncertain significance in ANKS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-06). AlphaMissense: likely benign (0.0713); Ultra-rare (popmax 0.0217%, nfe).

How common is ANKS3 p.Phe411Ser (c.1232T>C) in the general population?

ANKS3 p.Phe411Ser (c.1232T>C) is ultra-rare (popmax 0.0217%, nfe) (gnomAD).

What do computational predictors say about ANKS3 p.Phe411Ser (c.1232T>C)?

AlphaMissense predicts likely benign (score 0.0713) — an in-silico prediction, not a clinical call.

ANKS3 p.Phe411Ser

c.1232T>C · rs369241127 · VCV3126995

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0713 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0713	likely benign
REVEL	0.006	strongly benign-leaning
SaProt	LLR -3.88	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.58	GERP -3.6
Regional constraint	o/e 1.30	unconstrained · MANE · 33 kb · p 3.2e-19 · regional, not allelic
Overall
CADD	1.215	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0217% European (non-Finnish) · 256/1,179,994 alleles

Filtering AF 0.0195% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0186%

Overall 0.0173% 280/1,613,904 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0217%	4,609
Remaining individualsnot grpmax-eligible	0.0208%	4,807
Admixed American	0.00833%	12,000
African / African-American	0.00534%	18,728
Finnishnot grpmax-eligible	0.00156%	63,938
South Asian	0.0011%	91,082

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: ANKS3
Protein: p.Phe411Ser
Coding: c.1232T>C
MANE Select: NM_133450
dbSNP: rs369241127
Type: single nucleotide variant
Location: chr16:4701022 (GRCh38)
Gene constraint: LOEUF 1.102 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.94 · 2 PDB
Residue 411: the 'disordered' region; the 'interaction with nek7' region

Full ANKS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKS3 p.Cys168Gly Likely benign ★★ same type
ANKS3 p.Glu328= Benign ★★ same type
ANKS3 p.Gly25Glu Benign ★★ same type
ANKS3 p.His377= Benign ★★ same type
ANKS3 p.Leu14= Benign/Likely benign ★★ same type
ANKS3 p.Val585= Benign ★★ same type
ANKS3 p.Ala118Thr Uncertain significance ★ same type
ANKS3 p.Ala271Thr 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/anks3-p-phe411ser (accessed [today's date]).

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