Is PHEX p.Pro76Ala (c.226C>G) pathogenic?

PHEX p.Pro76Ala (c.226C>G) is classified Uncertain significance in PHEX (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-05). AlphaMissense: ambiguous (0.4057); Very rare (popmax 0.000784%, nfe); Associated with X-linked dominant hypophosphatemic rickets.

What condition is associated with PHEX p.Pro76Ala (c.226C>G)?

PHEX p.Pro76Ala (c.226C>G) is associated with X-linked dominant hypophosphatemic rickets (ClinVar).

How common is PHEX p.Pro76Ala (c.226C>G) in the general population?

PHEX p.Pro76Ala (c.226C>G) is very rare (popmax 0.000784%, 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.Pro76Ala (c.226C>G)?

AlphaMissense predicts ambiguous (score 0.4057) — an in-silico prediction, not a clinical call.

PHEX p.Pro76Ala

c.226C>G · rs201394441 · VCV1049289

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4057 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000784%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

X-linked dominant hypophosphatemic rickets

Computational evidence

Protein change
AlphaMissense	0.4057	ambiguous
REVEL	0.851	moderately pathogenic-leaning
SaProt	LLR -10.96	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	25.5	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 0.000784% European (non-Finnish) · 7/892,743 alleles

Filtering AF 0.000326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00021%

Overall 0.000579% 7/1,208,731 alleles · very rare exomes 7/1,095,147 · genomes 0/113,584 · joint denominator

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.Pro76Ala
Coding: c.226C>G
MANE Select: NM_000444
dbSNP: rs201394441
Type: single nucleotide variant
Location: chrX:22047088 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 76: 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-pro76ala (accessed [today's date]).

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