Is ANKS6 p.Arg656His (c.1967G>A) pathogenic?

ANKS6 p.Arg656His (c.1967G>A) is classified Uncertain significance in ANKS6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-28). AlphaMissense: likely benign (0.1161); Ultra-rare (popmax 0.0179%, mid); Associated with Inborn genetic diseases.

What condition is associated with ANKS6 p.Arg656His (c.1967G>A)?

ANKS6 p.Arg656His (c.1967G>A) is associated with Inborn genetic diseases, nephronophthisis 16 (ClinVar).

How common is ANKS6 p.Arg656His (c.1967G>A) in the general population?

ANKS6 p.Arg656His (c.1967G>A) is ultra-rare (popmax 0.0179%, mid) (gnomAD).

What do computational predictors say about ANKS6 p.Arg656His (c.1967G>A)?

AlphaMissense predicts likely benign (score 0.1161) — an in-silico prediction, not a clinical call.

ANKS6 p.Arg656His

c.1967G>A · VCV3596038

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1161 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0179%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1161	likely benign
REVEL	0.162	moderately benign-leaning
SaProt	LLR -6.88	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 7.5	GERP 2.5, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 60 kb · p 0.79 · regional, not allelic
Overall
CADD	26.5	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 0.0179% Middle Eastern · 1/5,600 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00179%

Overall 0.00246% 37/1,501,166 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0179%	5,600
African / African-American	0.00703%	14,223
Remaining individualsnot grpmax-eligible	0.00523%	19,118
European (non-Finnish)	0.00241%	41,449
Finnishnot grpmax-eligible	0.00163%	61,276

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.Arg656His
Coding: c.1967G>A
MANE Select: NM_173551
Type: single nucleotide variant
Location: chr9:98770901 (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 656: the 'disordered' region

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

Also linked: nephronophthisis 16

Similar variants

ANKS6 p.Arg656Cys Uncertain significance ★ ⚠ same residue
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

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-arg656his (accessed [today's date]).

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