Is PHEX p.Cys142Tyr (c.425G>A) pathogenic?

PHEX p.Cys142Tyr (c.425G>A) is classified Likely pathogenic in PHEX (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-08). AlphaMissense: likely pathogenic (0.9967); No allele count reported in gnomAD v4.1 (AN 1,165,677); Associated with X-linked dominant hypophosphatemic rickets.

What condition is associated with PHEX p.Cys142Tyr (c.425G>A)?

PHEX p.Cys142Tyr (c.425G>A) is associated with X-linked dominant hypophosphatemic rickets (ClinVar).

How common is PHEX p.Cys142Tyr (c.425G>A) in the general population?

PHEX p.Cys142Tyr (c.425G>A) is no allele count reported in gnomAD v4.1 (AN 1,165,677) (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.Cys142Tyr (c.425G>A)?

AlphaMissense predicts likely pathogenic (score 0.9967) — an in-silico prediction, not a clinical call.

PHEX p.Cys142Tyr

c.425G>A · VCV4685004

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9967 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,165,677)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked dominant hypophosphatemic rickets

Computational evidence

Protein change
AlphaMissense	0.9967	likely pathogenic ✓ concordant with ClinVar · top 3% in PHEX
REVEL	0.928	moderately pathogenic-leaning
SaProt	LLR -9.94	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	28.7	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

No allele count reported in gnomAD v4.1 (AN 1,165,677). 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.Cys142Tyr
Coding: c.425G>A
MANE Select: NM_000444
Type: single nucleotide variant
Location: chrX:22076463 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 142: a disulfide bond; a UniProt-annotated variant site (in xlhrd); 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 p.Cys142Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
PHEX p.Cys142Arg Pathogenic ★ same residue
PHEX p.Cys142Phe Pathogenic ★ ⚠ same residue
PHEX p.Cys142Ter 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

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-cys142tyr (accessed [today's date]).

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