Is PHEX p.Met1Ile (c.3G>A) pathogenic?

PHEX p.Met1Ile (c.3G>A) is classified Pathogenic in PHEX (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-04). No allele count reported in gnomAD v4.1 (AN 1,196,314); Associated with X-linked dominant hypophosphatemic rickets.

What condition is associated with PHEX p.Met1Ile (c.3G>A)?

PHEX p.Met1Ile (c.3G>A) is associated with X-linked dominant hypophosphatemic rickets (ClinVar).

How common is PHEX p.Met1Ile (c.3G>A) in the general population?

PHEX p.Met1Ile (c.3G>A) is no allele count reported in gnomAD v4.1 (AN 1,196,314) (gnomAD).

How is X-linked hypophosphatemia inherited?

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

PHEX p.Met1Ile

c.3G>A · rs1926865530 · VCV1686021

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

start-loss

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,196,314)

Conditions

X-linked dominant hypophosphatemic rickets

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function in a haploinsufficient gene (ClinGen)
REVEL	0.544	indeterminate
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Pangolin	Δ0.45	gain · loss 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,196,314). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PHEX
Protein: p.Met1Ile
Coding: c.3G>A
MANE Select: NM_000444
dbSNP: rs1926865530
Type: single nucleotide variant
Location: chrX:22033008 (GRCh38)
Structure: AlphaFold pLDDT 94.58

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.Met1Leu Pathogenic ★ same residue
PHEX p.Met1Thr 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
PHEX c.1173+5G>C 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-met1ile (accessed [today's date]).

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