Is PHEX p.Ser140Ter (c.419C>A) pathogenic?

PHEX p.Ser140Ter (c.419C>A) is classified Pathogenic in PHEX (ClinVar, Single submitter, 1 submitter). Very rare (popmax 0.000115%, nfe); Associated with X-linked dominant hypophosphatemic rickets.

What condition is associated with PHEX p.Ser140Ter (c.419C>A)?

PHEX p.Ser140Ter (c.419C>A) is associated with X-linked dominant hypophosphatemic rickets (ClinVar).

How common is PHEX p.Ser140Ter (c.419C>A) in the general population?

PHEX p.Ser140Ter (c.419C>A) is very rare (popmax 0.000115%, 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.Ser140Ter

c.419C>A · VCV3382100

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000115%, nfe)

Conditions

X-linked dominant hypophosphatemic rickets

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 4 of 22
Splicing
SpliceAI	Δ0.26	donor loss · deltas
Pangolin	Δ0.33	loss · gain 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.9	GERP 0.74, phastCons 1
Overall
CADD	37.0	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

Grpmax group 0.000115% European (non-Finnish) · 1/868,569 alleles

Overall 8.46e-05% 1/1,182,504 alleles · very rare exomes 1/1,068,594 · genomes 0/113,910 · 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.Ser140Ter
Coding: c.419C>A
MANE Select: NM_000444
Type: single nucleotide variant
Location: chrX:22076457 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 140: 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.Ser140= Likely benign ★★ same residue
PHEX p.Ser140Leu 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

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-ser140ter (accessed [today's date]).

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