Is KANK1 p.Pro76Ser (c.226C>T) pathogenic?

KANK1 p.Pro76Ser (c.226C>T) is classified Conflicting classifications of pathogenicity in KANK1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-11). AlphaMissense: likely benign (0.0635); Very rare (popmax 0.00525%, nfe); Associated with cerebral palsy, spastic quadriplegic, 2.

What condition is associated with KANK1 p.Pro76Ser (c.226C>T)?

KANK1 p.Pro76Ser (c.226C>T) is associated with cerebral palsy, spastic quadriplegic, 2 (ClinVar).

How common is KANK1 p.Pro76Ser (c.226C>T) in the general population?

KANK1 p.Pro76Ser (c.226C>T) is very rare (popmax 0.00525%, nfe) (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.Pro76Ser (c.226C>T)?

AlphaMissense predicts likely benign (score 0.0635) — an in-silico prediction, not a clinical call.

KANK1 p.Pro76Ser

c.226C>T · rs767269190 · VCV1398091

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0635 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00525%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebral palsy, spastic quadriplegic, 2

Computational evidence

Protein change
AlphaMissense	0.0635	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -6.32	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.26	GERP -5.6
Regional constraint	o/e 1.40	unconstrained · MANE · 68 kb · p 3.5e-62 · regional, not allelic
Overall
CADD	0.043	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 0.00525% European (non-Finnish) · 62/1,180,026 alleles

Filtering AF 0.00418% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.0039% 63/1,614,028 alleles · very rare exomes 58/1,461,864 · genomes 5/152,164 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00525%	19,033
South Asian	0.0011%	91,088

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.Pro76Ser
Coding: c.226C>T
MANE Select: NM_015158
dbSNP: rs767269190
Type: single nucleotide variant
Location: chr9:710992 (GRCh38)
Gene constraint: LOEUF 1.149 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.50 · 5 PDB
Residue 76: the 'disordered' region

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-pro76ser (accessed [today's date]).

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