Is PHEX p.Cys693Trp (c.2079C>G) pathogenic?

PHEX p.Cys693Trp (c.2079C>G) is classified Likely pathogenic in PHEX (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-01-07). AlphaMissense: likely pathogenic (0.999); Absent from gnomAD v4.1; Associated with X-linked dominant hypophosphatemic rickets.

What condition is associated with PHEX p.Cys693Trp (c.2079C>G)?

PHEX p.Cys693Trp (c.2079C>G) is associated with X-linked dominant hypophosphatemic rickets (ClinVar).

How common is PHEX p.Cys693Trp (c.2079C>G) in the general population?

PHEX p.Cys693Trp (c.2079C>G) 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.

What do computational predictors say about PHEX p.Cys693Trp (c.2079C>G)?

AlphaMissense predicts likely pathogenic (score 0.999) — an in-silico prediction, not a clinical call.

PHEX p.Cys693Trp

c.2079C>G · rs1064796845 · VCV424185

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked dominant hypophosphatemic rickets

Computational evidence

Protein change
AlphaMissense	0.999	likely pathogenic ✓ concordant with ClinVar · top 1% in PHEX
REVEL	0.835	moderately pathogenic-leaning
SaProt	LLR -12.30	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.41	GERP -1.1, phastCons 0.99
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	23.6	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

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.Cys693Trp
Coding: c.2079C>G
MANE Select: NM_000444
dbSNP: rs1064796845
Type: single nucleotide variant
Location: chrX:22245341 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 693: a disulfide bond; the peptidase m13 domain; a UniProt-annotated variant site (in xlhrd)

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 p.Cys693Ser Pathogenic/Likely pathogenic ★★ same residue
PHEX p.Cys693Tyr Pathogenic/Likely pathogenic ★★ same residue
PHEX p.Cys693Arg Likely pathogenic ★★ ⚠ same residue
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

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-cys693trp (accessed [today's date]).

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