Is PHEX p.Ala573Asp (c.1718C>A) pathogenic?

PHEX p.Ala573Asp (c.1718C>A) is classified Pathogenic/Likely pathogenic in PHEX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-19). AlphaMissense: likely pathogenic (0.9936); Very rare (popmax 8.48e-05%); Associated with X-linked dominant hypophosphatemic rickets.

What condition is associated with PHEX p.Ala573Asp (c.1718C>A)?

PHEX p.Ala573Asp (c.1718C>A) is associated with X-linked dominant hypophosphatemic rickets (ClinVar).

How common is PHEX p.Ala573Asp (c.1718C>A) in the general population?

PHEX p.Ala573Asp (c.1718C>A) is very rare (popmax 8.48e-05%) (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.Ala573Asp (c.1718C>A)?

AlphaMissense predicts likely pathogenic (score 0.9936) — an in-silico prediction, not a clinical call.

PHEX p.Ala573Asp

c.1718C>A · rs1556135308 · VCV438578

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9936 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked dominant hypophosphatemic rickets

Computational evidence

Protein change
AlphaMissense	0.9936	likely pathogenic ✓ concordant with ClinVar · top 5% in PHEX
REVEL	0.764	pathogenic-leaning
SaProt	LLR -11.92	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	28.8	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

Grpmax group 8.48e-05%

Overall 8.48e-05% 1/1,179,243 alleles · very rare exomes 1/1,065,546 · genomes 0/113,697 · 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: PHEX
Protein: p.Ala573Asp
Coding: c.1718C>A
MANE Select: NM_000444
dbSNP: rs1556135308
Type: single nucleotide variant
Location: chrX:22219053 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 573: 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.Ala573Val Likely pathogenic ★★ same residue
PHEX p.Ala573Thr Uncertain significance ★ ⚠ same residue
PHEX p.Ala573fs Pathogenic ★ same residue
PHEX p.Ala573Pro 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-ala573asp (accessed [today's date]).

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