Is PHEX p.Thr738= (c.2214G>A) pathogenic?

PHEX p.Thr738= (c.2214G>A) is classified Conflicting classifications of pathogenicity in PHEX (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-24). Ultra-rare (popmax 0.0503%, amr); Associated with X-linked dominant hypophosphatemic rickets.

What condition is associated with PHEX p.Thr738= (c.2214G>A)?

PHEX p.Thr738= (c.2214G>A) is associated with X-linked dominant hypophosphatemic rickets (ClinVar).

How common is PHEX p.Thr738= (c.2214G>A) in the general population?

PHEX p.Thr738= (c.2214G>A) is ultra-rare (popmax 0.0503%, amr) (gnomAD).

How is X-linked hypophosphatemia inherited?

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

PHEX p.Thr738=

c.2214G>A · rs140742016 · VCV195652

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0503%, amr)

Conditions

X-linked dominant hypophosphatemic rickets

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.59	GERP -4.8, phastCons 0.001
Overall
CADD	1.663	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0503% Admixed American · 23/45,731 alleles

Filtering AF 0.0343% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0291%

Overall 0.023% 277/1,206,940 alleles · ultra-rare exomes 240/1,094,979 · genomes 37/111,961 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0503%	1,988
European (non-Finnish)	0.0258%	3,880
Remaining individualsnot grpmax-eligible	0.0253%	3,957
Ashkenazi Jewishnot grpmax-eligible	0.0136%	7,338
Finnishnot grpmax-eligible	0.0129%	7,765
African / African-American	0.00525%	19,036

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.Thr738=
Coding: c.2214G>A
MANE Select: NM_000444
dbSNP: rs140742016
Type: single nucleotide variant
Location: chrX:22247917 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 738: 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.Thr738Met Conflicting classifications of pathogenicity ★ ⚠ 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-thr738 (accessed [today's date]).

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