Is KANK2 p.Pro324Ala (c.970C>G) pathogenic?

KANK2 p.Pro324Ala (c.970C>G) is classified Uncertain significance in KANK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely benign (0.0547); Very rare (popmax 0.004%, nfe).

How common is KANK2 p.Pro324Ala (c.970C>G) in the general population?

KANK2 p.Pro324Ala (c.970C>G) is very rare (popmax 0.004%, nfe) (gnomAD).

What do computational predictors say about KANK2 p.Pro324Ala (c.970C>G)?

AlphaMissense predicts likely benign (score 0.0547) — an in-silico prediction, not a clinical call.

KANK2 p.Pro324Ala

c.970C>G · rs776066667 · VCV2217222

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0547 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0547	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -6.46	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 7.3	GERP 5.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 28 kb · p 0.16 · regional, not allelic
Overall
CADD	15.67	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 0.004% European (non-Finnish) · 47/1,176,040 alleles

Filtering AF 0.00308% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00305% 49/1,606,134 alleles · very rare exomes 45/1,453,932 · genomes 4/152,202 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.004%	25,022
Remaining individualsnot grpmax-eligible	0.00322%	31,015

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: KANK2
Protein: p.Pro324Ala
Coding: c.970C>G
MANE Select: NM_001136191
dbSNP: rs776066667
Type: single nucleotide variant
Location: chr19:11193110 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.58 · 3 PDB
Residue 324: the 'disordered' region

Full KANK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KANK2 p.Pro324Leu Uncertain significance ★★ ⚠ same residue
KANK2 p.Pro324= Benign/Likely benign ★★ same residue
KANK2 p.Ala182Val Uncertain significance ★★ ⚠ same type
KANK2 p.Ala317Val Uncertain significance ★★ ⚠ same type
KANK2 p.Ala347Thr Uncertain significance ★★ ⚠ same type
KANK2 p.Ala351Thr Uncertain significance ★★ ⚠ same type
KANK2 p.Ala393Gly Uncertain significance ★★ ⚠ same type
KANK2 p.Ala653Val Uncertain significance ★★ ⚠ same type

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/kank2-p-pro324ala (accessed [today's date]).

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