Is KANK4 p.Val486Phe (c.1456G>T) pathogenic?

KANK4 p.Val486Phe (c.1456G>T) is classified Uncertain significance in KANK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-22). AlphaMissense: likely benign (0.0932); Very rare (popmax 8.47e-05%, nfe).

How common is KANK4 p.Val486Phe (c.1456G>T) in the general population?

KANK4 p.Val486Phe (c.1456G>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about KANK4 p.Val486Phe (c.1456G>T)?

AlphaMissense predicts likely benign (score 0.0932) — an in-silico prediction, not a clinical call.

KANK4 p.Val486Phe

c.1456G>T · VCV4837860

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0932 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0932	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -8.02	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 -0.11	GERP -0.057
Regional constraint	o/e 0.98	unconstrained · MANE · 37 kb · p 0.46 · regional, not allelic
Overall
CADD	6.349	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 8.47e-05% European (non-Finnish) · 1/1,180,026 alleles

Overall 6.2e-05% 1/1,614,158 alleles · very rare exomes 1/1,461,890 · genomes 0/152,268 · joint denominator

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: KANK4
Protein: p.Val486Phe
Coding: c.1456G>T
MANE Select: NM_181712
Type: single nucleotide variant
Location: chr1:62273648 (GRCh38)
Gene constraint: LOEUF 0.829 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.17

Full KANK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KANK4 p.Ala115Val Uncertain significance ★★ ⚠ same type
KANK4 p.Ala987Thr Uncertain significance ★★ ⚠ same type
KANK4 p.Arg336Met Uncertain significance ★★ ⚠ same type
KANK4 p.Arg471Cys Uncertain significance ★★ ⚠ same type
KANK4 p.Arg653Cys Uncertain significance ★★ ⚠ same type
KANK4 p.Arg790Gln Uncertain significance ★★ ⚠ same type
KANK4 p.Asp266Gly Uncertain significance ★★ ⚠ same type
KANK4 p.Asp459Val 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/kank4-p-val486phe (accessed [today's date]).

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