Is PHKB p.Arg614Ser (c.1840C>A) pathogenic?

PHKB p.Arg614Ser (c.1840C>A) is classified Uncertain significance in PHKB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-26). AlphaMissense: likely pathogenic (0.7653); Very rare (popmax 0.00401%, afr); Associated with Inborn genetic diseases.

What condition is associated with PHKB p.Arg614Ser (c.1840C>A)?

PHKB p.Arg614Ser (c.1840C>A) is associated with Inborn genetic diseases (ClinVar).

How common is PHKB p.Arg614Ser (c.1840C>A) in the general population?

PHKB p.Arg614Ser (c.1840C>A) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about PHKB p.Arg614Ser (c.1840C>A)?

AlphaMissense predicts likely pathogenic (score 0.7653) — an in-silico prediction, not a clinical call.

PHKB p.Arg614Ser

c.1840C>A · VCV3417766

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7653 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7653	likely pathogenic
REVEL	0.861	moderately pathogenic-leaning
SaProt	LLR -11.65	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 5.9	GERP 2.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 238 kb · p 0.5 · regional, not allelic
Overall
CADD	26.1	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 0.00401% African / African-American · 3/74,820 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,610,928 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.Arg614Ser
Coding: c.1840C>A
MANE Select: NM_000293
Type: single nucleotide variant
Location: chr16:47650586 (GRCh38)
Gene constraint: LOEUF 0.792 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.06 · 6 PDB

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.Arg614His Uncertain significance ★★ ⚠ same residue
PHKB p.Arg614Cys Uncertain significance ★ ⚠ same residue
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

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-arg614ser (accessed [today's date]).

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