Is ANKS6 p.Arg686Gln (c.2057G>A) pathogenic?

ANKS6 p.Arg686Gln (c.2057G>A) is classified Uncertain significance in ANKS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-29). AlphaMissense: likely benign (0.067); Very rare (popmax 0.00347%, nfe); Associated with nephronophthisis 16.

What condition is associated with ANKS6 p.Arg686Gln (c.2057G>A)?

ANKS6 p.Arg686Gln (c.2057G>A) is associated with nephronophthisis 16 (ClinVar).

How common is ANKS6 p.Arg686Gln (c.2057G>A) in the general population?

ANKS6 p.Arg686Gln (c.2057G>A) is very rare (popmax 0.00347%, nfe) (gnomAD).

How is Nephronophthisis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ANKS6 p.Arg686Gln (c.2057G>A)?

AlphaMissense predicts likely benign (score 0.067) — an in-silico prediction, not a clinical call.

ANKS6 p.Arg686Gln

c.2057G>A · rs978673028 · VCV2163785

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.067 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00347%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis 16

Computational evidence

Protein change
AlphaMissense	0.067	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -6.40	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 -1.4	GERP -3.6
Regional constraint	o/e 0.99	unconstrained · MANE · 60 kb · p 0.79 · regional, not allelic
Overall
CADD	13.22	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 0.00347% European (non-Finnish) · 41/1,180,028 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00273% 44/1,613,914 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00347%	28,781
Remaining individualsnot grpmax-eligible	0.0016%	62,470
African / African-American	0.00133%	74,938
South Asian	0.0011%	91,072

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.Arg686Gln
Coding: c.2057G>A
MANE Select: NM_173551
dbSNP: rs978673028
Type: single nucleotide variant
Location: chr9:98768166 (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 686: the 'disordered' region

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

Disease context

nephronophthisis 16 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

ANKS6 c.1973-3C>G Pathogenic/Likely pathogenic ★★ same condition
ANKS6 p.Arg461Ter Pathogenic/Likely pathogenic ★★ same condition
ANKS6 c.907+6C>T Uncertain significance ★★ same condition
ANKS6 p.Ala215Thr Uncertain significance ★★ ⚠ same condition
ANKS6 p.Ala215Val Uncertain significance ★★ ⚠ same condition
ANKS6 p.Ala249Thr Uncertain significance ★★ ⚠ same condition
ANKS6 p.Ala261Thr Uncertain significance ★★ ⚠ same condition
ANKS6 p.Ala350Thr 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-arg686gln (accessed [today's date]).

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