Is KANK2 p.Val754Ala (c.2261T>C) pathogenic?

KANK2 p.Val754Ala (c.2261T>C) is classified Uncertain significance in KANK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: ambiguous (0.4702); Very rare (popmax 0.00167%, amr).

How common is KANK2 p.Val754Ala (c.2261T>C) in the general population?

KANK2 p.Val754Ala (c.2261T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about KANK2 p.Val754Ala (c.2261T>C)?

AlphaMissense predicts ambiguous (score 0.4702) — an in-silico prediction, not a clinical call.

KANK2 p.Val754Ala

c.2261T>C · VCV4089627

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4702 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
AlphaMissense	0.4702	ambiguous
REVEL	0.347	indeterminate
SaProt	LLR -9.65	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 28 kb · p 0.16 · regional, not allelic
Overall
CADD	24.6	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 0.00167% Admixed American · 1/60,024 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00105% 17/1,611,458 alleles · very rare exomes 17/1,459,136 · genomes 0/152,322 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,024
Remaining individualsnot grpmax-eligible	0.0016%	62,496
European (non-Finnish)	0.00127%	78,668

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.Val754Ala
Coding: c.2261T>C
MANE Select: NM_001136191
Type: single nucleotide variant
Location: chr19:11170199 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.58 · 3 PDB
Residue 754: the 'interaction with ncoa1' region; an α-helix

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

Similar variants

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
KANK2 p.Arg105His 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-val754ala (accessed [today's date]).

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