Is PHKB p.Leu182Phe (c.544C>T) pathogenic?

PHKB p.Leu182Phe (c.544C>T) is classified Uncertain significance in PHKB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-25). AlphaMissense: likely pathogenic (0.813); Very rare (popmax 0.00274%, afr).

How common is PHKB p.Leu182Phe (c.544C>T) in the general population?

PHKB p.Leu182Phe (c.544C>T) is very rare (popmax 0.00274%, afr) (gnomAD).

What do computational predictors say about PHKB p.Leu182Phe (c.544C>T)?

AlphaMissense predicts likely pathogenic (score 0.813) — an in-silico prediction, not a clinical call.

PHKB p.Leu182Phe

c.544C>T · VCV3368190

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.813 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00274%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.813	likely pathogenic
REVEL	0.798	moderately pathogenic-leaning
SaProt	LLR -12.12	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 238 kb · p 0.5 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00274% African / African-American · 2/72,990 alleles

Filtering AF 0.000455% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00017%

Overall 0.000198% 3/1,513,288 alleles · very rare exomes 1/1,361,240 · genomes 2/152,048 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00274%	36,495
South Asian	0.00112%	88,972

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.Leu182Phe
Coding: c.544C>T
MANE Select: NM_000293
Type: single nucleotide variant
Location: chr16:47515551 (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 182: an α-helix

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

Similar variants

PHKB p.Leu182Arg Uncertain significance ★ ⚠ same residue
PHKB p.Leu182= Likely benign ★ 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

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-leu182phe (accessed [today's date]).

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