Is PHKB p.Ser261Ala (c.781T>G) pathogenic?

PHKB p.Ser261Ala (c.781T>G) is classified Uncertain significance in PHKB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-10-17). AlphaMissense: likely benign (0.1763); Ultra-rare (popmax 0.0701%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PHKB p.Ser261Ala (c.781T>G)?

PHKB p.Ser261Ala (c.781T>G) is associated with Inborn genetic diseases, glycogen storage disease IXb (ClinVar).

How common is PHKB p.Ser261Ala (c.781T>G) in the general population?

PHKB p.Ser261Ala (c.781T>G) is ultra-rare (popmax 0.0701%, nfe) (gnomAD).

What do computational predictors say about PHKB p.Ser261Ala (c.781T>G)?

AlphaMissense predicts likely benign (score 0.1763) — an in-silico prediction, not a clinical call.

PHKB p.Ser261Ala

c.781T>G · rs137946010 · VCV319341

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1763 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0701%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1763	likely benign
REVEL	0.662	pathogenic-leaning
SaProt	LLR -3.53	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 238 kb · p 0.5 · regional, not allelic
Overall
CADD	23.1	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 0.0701% European (non-Finnish) · 826/1,178,314 alleles

Filtering AF 0.0661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0645%

Overall 0.0529% 853/1,612,192 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0701%	1,427
Remaining individualsnot grpmax-eligible	0.0304%	3,286
African / African-American	0.0107%	9,374

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.Ser261Ala
Coding: c.781T>G
MANE Select: NM_000293
dbSNP: rs137946010
Type: single nucleotide variant
Location: chr16:47587674 (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

Also linked: glycogen storage disease IXb

Similar variants

PHKB p.Ser261= Likely benign ★ same residue
PHKB c.1127-2A>G Pathogenic/Likely pathogenic ★★ same condition
PHKB c.1364-2A>G Pathogenic ★★ same condition
PHKB c.1972-2A>G Pathogenic/Likely pathogenic ★★ same condition
PHKB c.2427+965A>C Pathogenic/Likely pathogenic ★★ same condition
PHKB c.2896-1G>T Pathogenic ★★ same condition
PHKB c.306-2A>G Pathogenic/Likely pathogenic ★★ same condition
PHKB p.Arg103Ter Pathogenic/Likely pathogenic ★★ 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-ser261ala (accessed [today's date]).

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