Is PHKB p.Glu166Lys (c.496G>A) pathogenic?

PHKB p.Glu166Lys (c.496G>A) is classified Uncertain significance in PHKB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-22). AlphaMissense: likely benign (0.0765); Very rare (popmax 0.00104%, nfe).

How common is PHKB p.Glu166Lys (c.496G>A) in the general population?

PHKB p.Glu166Lys (c.496G>A) is very rare (popmax 0.00104%, nfe) (gnomAD).

What do computational predictors say about PHKB p.Glu166Lys (c.496G>A)?

AlphaMissense predicts likely benign (score 0.0765) — an in-silico prediction, not a clinical call.

PHKB p.Glu166Lys

c.496G>A · rs774068671 · VCV2683363

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0765 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00104%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0765	likely benign
REVEL	0.567	indeterminate
SaProt	LLR -5.28	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 238 kb · p 0.5 · regional, not allelic
Overall
CADD	21.7	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 0.00104% European (non-Finnish) · 12/1,150,848 alleles

Filtering AF 0.000556% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000439%

Overall 0.000758% 12/1,582,114 alleles · very rare exomes 12/1,429,884 · genomes 0/152,230 · 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: PHKB
Protein: p.Glu166Lys
Coding: c.496G>A
MANE Select: NM_000293
dbSNP: rs774068671
Type: single nucleotide variant
Location: chr16:47511755 (GRCh38)
Gene constraint: LOEUF 0.792 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.06 · 6 PDB
Residue 166: a turn

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

Similar variants

PHKB p.Glu166Ter Pathogenic ★ same residue
PHKB c.1127-2A>G Pathogenic/Likely pathogenic ★★ same type
PHKB c.1364-2A>G Pathogenic ★★ same type
PHKB c.1972-2A>G Pathogenic/Likely pathogenic ★★ same type
PHKB c.2427+965A>C Pathogenic/Likely pathogenic ★★ same type
PHKB c.2896-1G>T Pathogenic ★★ same type
PHKB c.306-2A>G Pathogenic/Likely pathogenic ★★ same type
PHKB p.Arg103Ter Pathogenic/Likely pathogenic ★★ 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/phkb-p-glu166lys (accessed [today's date]).

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