Is PHEX p.Thr461= (c.1383G>A) pathogenic?

PHEX p.Thr461= (c.1383G>A) is classified Benign/Likely benign in PHEX (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-06). Low-frequency (popmax 1.2%, afr); Associated with X-linked dominant hypophosphatemic rickets.

What condition is associated with PHEX p.Thr461= (c.1383G>A)?

PHEX p.Thr461= (c.1383G>A) is associated with X-linked dominant hypophosphatemic rickets (ClinVar).

How common is PHEX p.Thr461= (c.1383G>A) in the general population?

PHEX p.Thr461= (c.1383G>A) is low-frequency (popmax 1.2%, afr) (gnomAD).

How is X-linked hypophosphatemia inherited?

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

PHEX p.Thr461=

c.1383G>A · rs77710864 · VCV733250

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.2%, afr)

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 -0.029	GERP -2.9, phastCons 0.072
Overall
CADD	1.874	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.2% African / African-American · 680/56,673 alleles

Filtering AF 1.13% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1%

Overall 0.078% 935/1,198,526 alleles · low-frequency exomes 529/1,087,703 · genomes 406/110,823 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.2%	83
Middle Eastern	0.255%	392
Admixed American	0.147%	680
Remaining individualsnot grpmax-eligible	0.114%	875
East Asian	0.0386%	2,591
European (non-Finnish)	0.0119%	8,434
South Asian	0.00709%	14,106
Finnishnot grpmax-eligible	0.00216%	46,400

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.Thr461=
Coding: c.1383G>A
MANE Select: NM_000444
dbSNP: rs77710864
Type: single nucleotide variant
Location: chrX:22133603 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 461: 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.Thr461Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
PHEX p.Thr461Met Uncertain significance ★★ ⚠ same residue
PHEX p.Thr461Arg 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

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-thr461 (accessed [today's date]).

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