Is ANKS6 p.Ala333Ser (c.997G>T) pathogenic?

ANKS6 p.Ala333Ser (c.997G>T) is classified Uncertain significance in ANKS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-28). AlphaMissense: ambiguous (0.3479); Very rare (popmax 0.00153%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ANKS6 p.Ala333Ser (c.997G>T)?

ANKS6 p.Ala333Ser (c.997G>T) is associated with Inborn genetic diseases (ClinVar).

How common is ANKS6 p.Ala333Ser (c.997G>T) in the general population?

ANKS6 p.Ala333Ser (c.997G>T) is very rare (popmax 0.00153%, nfe) (gnomAD).

What do computational predictors say about ANKS6 p.Ala333Ser (c.997G>T)?

AlphaMissense predicts ambiguous (score 0.3479) — an in-silico prediction, not a clinical call.

ANKS6 p.Ala333Ser

c.997G>T · VCV4580856

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3479 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3479	ambiguous
REVEL	0.643	indeterminate
SaProt	LLR -8.91	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 60 kb · p 0.79 · regional, not allelic
Overall
CADD	24.4	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 0.00153% European (non-Finnish) · 18/1,178,536 alleles

Filtering AF 0.000955% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000788%

Overall 0.00118% 19/1,610,708 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00153%	65,474
African / African-American	0.00133%	74,964

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: ANKS6
Protein: p.Ala333Ser
Coding: c.997G>T
MANE Select: NM_173551
Type: single nucleotide variant
Location: chr9:98784068 (GRCh38)
Gene constraint: LOEUF 0.869 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.60 · 1 PDB

Full ANKS6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ANKS6 p.Ala333Val Uncertain significance ★ ⚠ same residue
ANKS6 p.Ala333= Likely benign ★ same residue
ANKS6 p.Ala363Val Uncertain significance ★★ ⚠ same condition
ANKS6 p.Ala589Glu Uncertain significance ★★ ⚠ same condition
ANKS6 p.Ala64Pro Uncertain significance ★★ ⚠ same condition
ANKS6 p.Ala835Thr Uncertain significance ★★ ⚠ same condition
ANKS6 p.Ala9Val Uncertain significance ★★ ⚠ same condition
ANKS6 p.Arg142Gln Uncertain significance ★★ ⚠ same condition

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/anks6-p-ala333ser (accessed [today's date]).

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