Is ANKS6 p.Asp820Ala (c.2459A>C) pathogenic?

ANKS6 p.Asp820Ala (c.2459A>C) is classified Uncertain significance in ANKS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-08). AlphaMissense: ambiguous (0.5193); Very rare (popmax 0.000763%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ANKS6 p.Asp820Ala (c.2459A>C)?

ANKS6 p.Asp820Ala (c.2459A>C) is associated with Inborn genetic diseases (ClinVar).

How common is ANKS6 p.Asp820Ala (c.2459A>C) in the general population?

ANKS6 p.Asp820Ala (c.2459A>C) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about ANKS6 p.Asp820Ala (c.2459A>C)?

AlphaMissense predicts ambiguous (score 0.5193) — an in-silico prediction, not a clinical call.

ANKS6 p.Asp820Ala

c.2459A>C · VCV3874640

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5193 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5193	ambiguous
REVEL	0.402	indeterminate
SaProt	LLR -5.07	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.57 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 0.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 60 kb · p 0.79 · regional, not allelic
Overall
CADD	26.7	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 0.000763% European (non-Finnish) · 9/1,180,028 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,614,034 alleles · very rare

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.Asp820Ala
Coding: c.2459A>C
MANE Select: NM_173551
Type: single nucleotide variant
Location: chr9:98745611 (GRCh38)
Gene constraint: LOEUF 0.869 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.60 · 1 PDB
Residue 820: the sam domain; an α-helix

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.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
ANKS6 p.Arg153Trp Uncertain significance ★★ same condition
ANKS6 p.Arg427Trp 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-asp820ala (accessed [today's date]).

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