Is PHKB p.Ser704fs (c.2109del) pathogenic?

PHKB p.Ser704fs (c.2109del) is classified Pathogenic in PHKB (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-16). Very rare (popmax 8.48e-05%, nfe); Associated with mitochondrial disease.

What condition is associated with PHKB p.Ser704fs (c.2109del)?

PHKB p.Ser704fs (c.2109del) is associated with mitochondrial disease (ClinVar).

How common is PHKB p.Ser704fs (c.2109del) in the general population?

PHKB p.Ser704fs (c.2109del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

PHKB p.Ser704fs

c.2109del · VCV4074851

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

mitochondrial disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 22 of 31
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.2	GERP 1.2, phastCons 0.009

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,578 alleles

Overall 6.2e-05% 1/1,613,682 alleles · very rare exomes 1/1,461,384 · genomes 0/152,298 · joint denominator

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.Ser704fs
Coding: c.2109del
MANE Select: NM_000293
Type: Deletion
Location: chr16:47660732 (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 704: the 'disordered' region

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

Disease context

mitochondrial disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PHKB c.2427+977C>T Conflicting classifications of pathogenicity ★ same condition
PHKB p.Glu820fs Pathogenic/Likely pathogenic ★★ same type
PHKB p.Val175fs Pathogenic/Likely pathogenic ★★ same type
PHKB c.1881-52_1881-49del Benign/Likely benign ★★ same type
PHKB c.2427+964del Likely benign ★★ same type
PHKB c.3144+34del Benign/Likely benign ★★ same type
PHKB c.1363+1del Likely pathogenic ★ same type
PHKB c.167-6_170del 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-ser704fs (accessed [today's date]).

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