Is PHEX p.Lys221= (c.663G>A) pathogenic?

PHEX p.Lys221= (c.663G>A) is classified Pathogenic/Likely pathogenic in PHEX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-04). Absent from gnomAD v4.1; Associated with X-linked dominant hypophosphatemic rickets.

What condition is associated with PHEX p.Lys221= (c.663G>A)?

PHEX p.Lys221= (c.663G>A) is associated with X-linked dominant hypophosphatemic rickets (ClinVar).

How common is PHEX p.Lys221= (c.663G>A) in the general population?

PHEX p.Lys221= (c.663G>A) is absent from gnomAD v4.1 (gnomAD).

How is X-linked hypophosphatemia inherited?

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

PHEX p.Lys221=

c.663G>A · rs1929220357 · VCV944842

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

X-linked dominant hypophosphatemic rickets

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.85	donor loss · deltas
Pangolin	Δ0.80	loss · gain 0.15 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PHEX
Protein: p.Lys221=
Coding: c.663G>A
MANE Select: NM_000444
dbSNP: rs1929220357
Type: single nucleotide variant
Location: chrX:22077702 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 221: 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.1079+1G>A Pathogenic ★★ same condition
PHEX c.1079+2T>G Pathogenic ★★ same condition
PHEX c.1080-1G>A Pathogenic ★★ same condition
PHEX c.1080-3C>G Pathogenic ★★ same condition
PHEX c.1173+1G>A Pathogenic ★★ same condition
PHEX c.1173+5G>C Likely pathogenic ★★ same condition
PHEX c.1174-1G>A Pathogenic ★★ same condition
PHEX c.118+1G>A 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/phex-p-lys221 (accessed [today's date]).

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