Is PHKB p.Arg131His (c.392G>A) pathogenic?

PHKB p.Arg131His (c.392G>A) is classified Uncertain significance in PHKB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-03). AlphaMissense: likely benign (0.3157); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with PHKB p.Arg131His (c.392G>A)?

PHKB p.Arg131His (c.392G>A) is associated with Inborn genetic diseases (ClinVar).

How common is PHKB p.Arg131His (c.392G>A) in the general population?

PHKB p.Arg131His (c.392G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about PHKB p.Arg131His (c.392G>A)?

AlphaMissense predicts likely benign (score 0.3157) — an in-silico prediction, not a clinical call.

PHKB p.Arg131His

c.392G>A · VCV3359841

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3157 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3157	likely benign
REVEL	0.886	moderately pathogenic-leaning
SaProt	LLR -11.80	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 238 kb · p 0.5 · regional, not allelic
Overall
CADD	32.0	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 0.0165% Middle Eastern · 1/6,066 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00313%

Overall 0.00356% 57/1,601,484 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,066
South Asian	0.00881%	11,349
Admixed American	0.005%	19,993
European (non-Finnish)	0.00368%	27,178
Remaining individualsnot grpmax-eligible	0.00322%	31,042

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.Arg131His
Coding: c.392G>A
MANE Select: NM_000293
Type: single nucleotide variant
Location: chr16:47503077 (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.Arg131Cys Conflicting classifications of pathogenicity ★ ⚠ 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.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-arg131his (accessed [today's date]).

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