Is PHEX p.Ser228fs (c.682_683del) pathogenic?

PHEX p.Ser228fs (c.682683del) is classified Pathogenic in PHEX (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-02-17). No gnomAD frequency available for this variant; Associated with X-linked dominant hypophosphatemic rickets.

What condition is associated with PHEX p.Ser228fs (c.682_683del)?

PHEX p.Ser228fs (c.682_683del) is associated with X-linked dominant hypophosphatemic rickets (ClinVar).

How common is PHEX p.Ser228fs (c.682_683del) in the general population?

PHEX p.Ser228fs (c.682_683del) is no gnomAD frequency available for this variant (gnomAD).

How is X-linked hypophosphatemia inherited?

Typically X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

PHEX p.Ser228fs

c.682_683del · rs1064793956 · VCV419563

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

X-linked dominant hypophosphatemic rickets

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 6 of 22
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2.2	GERP -3.5

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PHEX
Protein: p.Ser228fs
Coding: c.682_683del
MANE Select: NM_000444
dbSNP: rs1064793956
Type: Microsatellite
Location: chrX:22090444 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 228: the peptidase m13 domain

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

Disease context

X-linked dominant hypophosphatemic rickets — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For X-linked hypophosphatemia (Orphanet):

Inheritance: X-linked dominant
Onset: Childhood, Infancy
Prevalence: 1-9 / 100 000 (Norway)

Similar variants

PHEX c.1586_1586+1del Pathogenic ★★ same condition
PHEX p.Lys320del Pathogenic/Likely pathogenic ★★ same condition
PHEX p.Phe560fs Likely pathogenic ★★ same condition
PHEX p.Val70fs Pathogenic ★★ same condition
PHEX p.Arg183fs Pathogenic ★ same condition
PHEX c.1586+3_1586+6del Conflicting classifications of pathogenicity ★ same condition
PHEX c.1079+1G>A Pathogenic ★★ same condition
PHEX c.1079+2_1079+5del 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/phex-p-ser228fs (accessed [today's date]).

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