Is KANK2 p.Ala346= (c.1038C>T) pathogenic?

KANK2 p.Ala346= (c.1038C>T) is classified Benign/Likely benign in KANK2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-26). Low-frequency (popmax 3.73%, eas); Associated with nephrotic syndrome 16.

What condition is associated with KANK2 p.Ala346= (c.1038C>T)?

KANK2 p.Ala346= (c.1038C>T) is associated with nephrotic syndrome 16, wooly hair-palmoplantar keratoderma syndrome (ClinVar).

How common is KANK2 p.Ala346= (c.1038C>T) in the general population?

KANK2 p.Ala346= (c.1038C>T) is low-frequency (popmax 3.73%, eas) (gnomAD).

KANK2 p.Ala346=

c.1038C>T · rs118109949 · VCV715318

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.73%, eas)

Conditions

nephrotic syndrome 16

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -8.7	GERP -11
Overall
CADD	0.354	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.73% East Asian · 1,670/44,800 alleles

Filtering AF 3.58% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.52%

Overall 0.204% 3,283/1,611,512 alleles · low-frequency exomes 2,938/1,459,410 · genomes 345/152,102 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	3.73%	27
Middle Eastern	0.663%	151
South Asian	0.497%	201
Remaining individualsnot grpmax-eligible	0.332%	301
Ashkenazi Jewishnot grpmax-eligible	0.271%	369
Admixed American	0.12%	831
European (non-Finnish)	0.0629%	1,589
African / African-American	0.0254%	3,943
Finnishnot grpmax-eligible	0.00158%	63,224

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.Ala346=
Coding: c.1038C>T
MANE Select: NM_001136191
dbSNP: rs118109949
Type: single nucleotide variant
Location: chr19:11193042 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.58 · 3 PDB

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

Disease context

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

Also linked: wooly hair-palmoplantar keratoderma syndrome

Similar variants

KANK2 p.Arg326His Uncertain significance ★★ ⚠ same condition
KANK2 p.Gly690Ser Uncertain significance ★★ ⚠ same condition
KANK2 p.Pro457Ser Uncertain significance ★★ ⚠ same condition
KANK2 p.Ser848Leu Uncertain significance ★★ ⚠ same condition
KANK2 p.Val502Met Uncertain significance ★★ ⚠ same condition
KANK2 c.2502+15G>A Benign/Likely benign ★★ same condition
KANK2 p.Val4Ile Likely benign ★★ same condition
KANK2 p.Arg380Cys Conflicting classifications of pathogenicity ★ ⚠ 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/kank2-p-ala346 (accessed [today's date]).

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