Is PHEX p.Pro401Leu (c.1202C>T) pathogenic?

PHEX p.Pro401Leu (c.1202C>T) is classified Conflicting classifications of pathogenicity in PHEX (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-29). AlphaMissense: ambiguous (0.3537); Ultra-rare (popmax 0.0333%, nfe); Associated with X-linked dominant hypophosphatemic rickets.

What condition is associated with PHEX p.Pro401Leu (c.1202C>T)?

PHEX p.Pro401Leu (c.1202C>T) is associated with X-linked dominant hypophosphatemic rickets, intellectual disability (ClinVar).

How common is PHEX p.Pro401Leu (c.1202C>T) in the general population?

PHEX p.Pro401Leu (c.1202C>T) is ultra-rare (popmax 0.0333%, 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.Pro401Leu (c.1202C>T)?

AlphaMissense predicts ambiguous (score 0.3537) — an in-silico prediction, not a clinical call.

PHEX p.Pro401Leu

c.1202C>T · rs145778165 · VCV286845

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.3537 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

X-linked dominant hypophosphatemic rickets

Computational evidence

Protein change
AlphaMissense	0.3537	ambiguous
REVEL	0.669	pathogenic-leaning
SaProt	LLR -11.44	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	25.6	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 0.0333% European (non-Finnish) · 294/883,175 alleles

Filtering AF 0.0301% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0289%

Overall 0.027% 323/1,196,531 alleles · ultra-rare exomes 301/1,084,918 · genomes 22/111,613 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0403%	2,483
European (non-Finnish)grpmax	0.0333%	3,004
Admixed American	0.011%	9,125
African / African-American	0.00527%	18,967
Finnishnot grpmax-eligible	0.0043%	23,241

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro401Leu
Coding: c.1202C>T
MANE Select: NM_000444
dbSNP: rs145778165
Type: single nucleotide variant
Location: chrX:22114486 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 401: 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

Also linked: intellectual disability

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-pro401leu (accessed [today's date]).

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