Is PHKB p.Val574Ala (c.1721T>C) pathogenic?

PHKB p.Val574Ala (c.1721T>C) is classified Uncertain significance in PHKB (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-12). AlphaMissense: ambiguous (0.3699); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with PHKB p.Val574Ala (c.1721T>C)?

PHKB p.Val574Ala (c.1721T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PHKB p.Val574Ala (c.1721T>C) in the general population?

PHKB p.Val574Ala (c.1721T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PHKB p.Val574Ala (c.1721T>C)?

AlphaMissense predicts ambiguous (score 0.3699) — an in-silico prediction, not a clinical call.

PHKB p.Val574Ala

c.1721T>C · VCV4832931

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3699 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3699	ambiguous
REVEL	0.774	moderately pathogenic-leaning
SaProt	LLR -8.71	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 238 kb · p 0.5 · regional, not allelic
Overall
CADD	26.0	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 0.00133% African / African-American · 1/74,938 alleles

Overall 6.87e-05% 1/1,455,502 alleles · very rare

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.Val574Ala
Coding: c.1721T>C
MANE Select: NM_000293
Type: single nucleotide variant
Location: chr16:47649128 (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 574: a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PHKB p.Ala1072Thr Uncertain significance ★★ ⚠ same condition
PHKB p.Ala781Val Uncertain significance ★★ ⚠ same condition
PHKB p.Ala787Pro Uncertain significance ★★ ⚠ same condition
PHKB p.Ala9Thr Uncertain significance ★★ ⚠ same condition
PHKB p.Arg103Gln Uncertain significance ★★ ⚠ same condition
PHKB p.Arg131His Uncertain significance ★★ ⚠ same condition
PHKB p.Arg144Cys Uncertain significance ★★ ⚠ same condition
PHKB p.Arg214His Uncertain significance ★★ ⚠ same condition

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-val574ala (accessed [today's date]).

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