Is KANK2 p.Ser425Leu (c.1274C>T) pathogenic?

KANK2 p.Ser425Leu (c.1274C>T) is classified Likely benign in KANK2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-10-29). AlphaMissense: likely benign (0.079); Rare (popmax 0.493%, afr).

How common is KANK2 p.Ser425Leu (c.1274C>T) in the general population?

KANK2 p.Ser425Leu (c.1274C>T) is rare (popmax 0.493%, afr) (gnomAD).

What do computational predictors say about KANK2 p.Ser425Leu (c.1274C>T)?

AlphaMissense predicts likely benign (score 0.079) — an in-silico prediction, not a clinical call.

KANK2 p.Ser425Leu

c.1274C>T · rs143873045 · VCV2137800

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.079 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.493%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.079	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -7.08	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 1.5	GERP 3.1, phastCons 0.003
Regional constraint	o/e 0.96	unconstrained · MANE · 28 kb · p 0.16 · regional, not allelic
Overall
CADD	6.458	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 0.493% African / African-American · 346/70,164 alleles

Filtering AF 0.45% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.433%

Overall 0.0273% 420/1,537,442 alleles · rare exomes 209/1,385,128 · genomes 211/152,314 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.493%	203
Remaining individualsnot grpmax-eligible	0.0389%	2,571
Admixed American	0.0209%	4,784
South Asian	0.0199%	5,015
European (non-Finnish)	0.00227%	44,135

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.Ser425Leu
Coding: c.1274C>T
MANE Select: NM_001136191
dbSNP: rs143873045
Type: single nucleotide variant
Location: chr19:11178696 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.58 · 3 PDB
Residue 425: the 'disordered' region

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

Similar variants

KANK2 p.Ser425= 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
KANK2 p.Ala711Val 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-ser425leu (accessed [today's date]).

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