Is PHEX p.Lys319= (c.957G>A) pathogenic?

PHEX p.Lys319= (c.957G>A) is classified Conflicting classifications of pathogenicity in PHEX (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-06-17). Ultra-rare (popmax 0.0232%, nfe); Associated with X-linked dominant hypophosphatemic rickets.

What condition is associated with PHEX p.Lys319= (c.957G>A)?

PHEX p.Lys319= (c.957G>A) is associated with X-linked dominant hypophosphatemic rickets (ClinVar).

How common is PHEX p.Lys319= (c.957G>A) in the general population?

PHEX p.Lys319= (c.957G>A) is ultra-rare (popmax 0.0232%, 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.Lys319=

c.957G>A · rs373261521 · VCV368164

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 0.0232%, 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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.4	GERP 0.5, phastCons 1
Overall
CADD	13.07	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0232% European (non-Finnish) · 207/893,654 alleles

Filtering AF 0.0205% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0196%

Overall 0.0185% 223/1,206,943 alleles · ultra-rare exomes 211/1,096,561 · genomes 12/110,382 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0252%	3,962
European (non-Finnish)grpmax	0.0232%	4,317
African / African-American	0.00529%	18,892
Admixed American	0.0022%	45,511

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Lys319=
Coding: c.957G>A
MANE Select: NM_000444
dbSNP: rs373261521
Type: single nucleotide variant
Location: chrX:22099029 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 319: 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.Lys319Thr Uncertain significance ★ ⚠ 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-lys319 (accessed [today's date]).

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