Is PHEX p.Ala720Glu (c.2159C>A) pathogenic?

PHEX p.Ala720Glu (c.2159C>A) is classified Likely pathogenic in PHEX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2017-01-06). AlphaMissense: likely pathogenic (0.9585); No allele count reported in gnomAD v4.1 (AN 1,198,039); Associated with X-linked dominant hypophosphatemic rickets.

What condition is associated with PHEX p.Ala720Glu (c.2159C>A)?

PHEX p.Ala720Glu (c.2159C>A) is associated with X-linked dominant hypophosphatemic rickets (ClinVar).

How common is PHEX p.Ala720Glu (c.2159C>A) in the general population?

PHEX p.Ala720Glu (c.2159C>A) is no allele count reported in gnomAD v4.1 (AN 1,198,039) (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.Ala720Glu (c.2159C>A)?

AlphaMissense predicts likely pathogenic (score 0.9585) — an in-silico prediction, not a clinical call.

PHEX p.Ala720Glu

c.2159C>A · rs1057517798 · VCV372464

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9585 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,198,039)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked dominant hypophosphatemic rickets

Computational evidence

Protein change
AlphaMissense	0.9585	likely pathogenic ✓ concordant with ClinVar
REVEL	0.781	moderately pathogenic-leaning
SaProt	LLR -11.35	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 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	26.7	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 1,198,039). 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.Ala720Glu
Coding: c.2159C>A
MANE Select: NM_000444
dbSNP: rs1057517798
Type: single nucleotide variant
Location: chrX:22247862 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 720: 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.Ala720Thr 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
PHEX c.1173+5G>C Likely pathogenic ★★ same condition
PHEX c.1174-1G>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-ala720glu (accessed [today's date]).

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