Is KANK1 p.Pro784Arg (c.2351C>G) pathogenic?

KANK1 p.Pro784Arg (c.2351C>G) is classified Uncertain significance in KANK1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.1591); Ultra-rare (popmax 0.0166%, mid); Associated with cerebral palsy, spastic quadriplegic, 2.

What condition is associated with KANK1 p.Pro784Arg (c.2351C>G)?

KANK1 p.Pro784Arg (c.2351C>G) is associated with cerebral palsy, spastic quadriplegic, 2 (ClinVar).

How common is KANK1 p.Pro784Arg (c.2351C>G) in the general population?

KANK1 p.Pro784Arg (c.2351C>G) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

How is Inherited congenital spastic tetraplegia inherited?

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

What do computational predictors say about KANK1 p.Pro784Arg (c.2351C>G)?

AlphaMissense predicts likely benign (score 0.1591) — an in-silico prediction, not a clinical call.

KANK1 p.Pro784Arg

c.2351C>G · VCV3891434

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1591 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebral palsy, spastic quadriplegic, 2

Computational evidence

Protein change
AlphaMissense	0.1591	likely benign
REVEL	0.271	benign-leaning
SaProt	LLR -6.55	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 5.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.40	unconstrained · MANE · 68 kb · p 3.5e-62 · regional, not allelic
Overall
CADD	23.6	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 0.0166% Middle Eastern · 1/6,008 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000249% 4/1,604,750 alleles · ultra-rare exomes 4/1,452,420 · genomes 0/152,330 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,008
Remaining individualsnot grpmax-eligible	0.00161%	62,088
European (non-Finnish)	0.00017%	586,775

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: KANK1
Protein: p.Pro784Arg
Coding: c.2351C>G
MANE Select: NM_015158
Type: single nucleotide variant
Location: chr9:713117 (GRCh38)
Gene constraint: LOEUF 1.149 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.50 · 5 PDB

Full KANK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cerebral palsy, spastic quadriplegic, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Inherited congenital spastic tetraplegia (Orphanet):

Inheritance: Autosomal recessive, Unknown
Onset: Infancy, Neonatal

Similar variants

KANK1 c.2896+2T>G Uncertain significance ★★ same condition
KANK1 p.Ala1184= Uncertain significance ★★ same condition
KANK1 p.Ala1203Val Uncertain significance ★★ ⚠ same condition
KANK1 p.Ala1255Asp Uncertain significance ★★ ⚠ same condition
KANK1 p.Ala228Gly Uncertain significance ★★ ⚠ same condition
KANK1 p.Ala718Gly Uncertain significance ★★ ⚠ same condition
KANK1 p.Arg420Ser Uncertain significance ★★ ⚠ same condition
KANK1 p.Arg471His 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/kank1-p-pro784arg (accessed [today's date]).

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