Is PHEX p.Val506Ile (c.1516G>A) pathogenic?

PHEX p.Val506Ile (c.1516G>A) is classified Conflicting classifications of pathogenicity in PHEX (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0837); Very rare (popmax 0.00855%, nfe); Associated with X-linked dominant hypophosphatemic rickets.

What condition is associated with PHEX p.Val506Ile (c.1516G>A)?

PHEX p.Val506Ile (c.1516G>A) is associated with X-linked dominant hypophosphatemic rickets (ClinVar).

How common is PHEX p.Val506Ile (c.1516G>A) in the general population?

PHEX p.Val506Ile (c.1516G>A) is very rare (popmax 0.00855%, nfe) (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.Val506Ile (c.1516G>A)?

AlphaMissense predicts likely benign (score 0.0837) — an in-silico prediction, not a clinical call.

PHEX p.Val506Ile

c.1516G>A · rs781248973 · VCV2981663

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0837 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00855%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

X-linked dominant hypophosphatemic rickets

Computational evidence

Protein change
AlphaMissense	0.0837	likely benign
REVEL	0.392	indeterminate
SaProt	LLR -5.84	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP -0.48, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	22.8	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

Grpmax group 0.00855% European (non-Finnish) · 76/889,117 alleles

Filtering AF 0.007% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00639%

Overall 0.00657% 79/1,202,083 alleles · very rare exomes 78/1,089,896 · genomes 1/112,187 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00855%	11,699
Remaining individualsnot grpmax-eligible	0.00424%	23,589
African / African-American	0.00175%	57,114

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.Val506Ile
Coding: c.1516G>A
MANE Select: NM_000444
dbSNP: rs781248973
Type: single nucleotide variant
Location: chrX:22178306 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 506: 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-val506ile (accessed [today's date]).

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