Is PHEX p.Ile148= (c.444T>C) pathogenic?

PHEX p.Ile148= (c.444T>C) is classified Conflicting classifications of pathogenicity in PHEX (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-03). Ultra-rare (popmax 0.0106%, nfe); Associated with X-linked dominant hypophosphatemic rickets.

What condition is associated with PHEX p.Ile148= (c.444T>C)?

PHEX p.Ile148= (c.444T>C) is associated with X-linked dominant hypophosphatemic rickets (ClinVar).

How common is PHEX p.Ile148= (c.444T>C) in the general population?

PHEX p.Ile148= (c.444T>C) is ultra-rare (popmax 0.0106%, nfe) (gnomAD).

How is X-linked hypophosphatemia inherited?

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

PHEX p.Ile148=

c.444T>C · rs145881500 · VCV749634

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0106%, nfe)

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 -4.3	GERP -3.2
Overall
CADD	0.699	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0106% European (non-Finnish) · 95/893,150 alleles

Filtering AF 0.00888% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00825%

Overall 0.00819% 99/1,208,058 alleles · ultra-rare exomes 90/1,095,780 · genomes 9/112,278 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0106%	9,402
Finnishnot grpmax-eligible	0.00428%	23,357
Remaining individualsnot grpmax-eligible	0.0021%	47,523
African / African-American	0.00175%	57,227

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.Ile148=
Coding: c.444T>C
MANE Select: NM_000444
dbSNP: rs145881500
Type: single nucleotide variant
Location: chrX:22077483 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 148: 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 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
PHEX c.118+1G>A Pathogenic/Likely 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-ile148 (accessed [today's date]).

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