Is PHEX p.Arg381His (c.1142G>A) pathogenic?

PHEX p.Arg381His (c.1142G>A) is classified Uncertain significance in PHEX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). AlphaMissense: ambiguous (0.3727); Ultra-rare (popmax 0.0122%, afr); Associated with X-linked dominant hypophosphatemic rickets.

What condition is associated with PHEX p.Arg381His (c.1142G>A)?

PHEX p.Arg381His (c.1142G>A) is associated with X-linked dominant hypophosphatemic rickets (ClinVar).

How common is PHEX p.Arg381His (c.1142G>A) in the general population?

PHEX p.Arg381His (c.1142G>A) is ultra-rare (popmax 0.0122%, afr) (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.Arg381His (c.1142G>A)?

AlphaMissense predicts ambiguous (score 0.3727) — an in-silico prediction, not a clinical call.

PHEX p.Arg381His

c.1142G>A · VCV3598230

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3727 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

X-linked dominant hypophosphatemic rickets

Computational evidence

Protein change
AlphaMissense	0.3727	ambiguous
REVEL	0.722	pathogenic-leaning
SaProt	LLR -9.59	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	28.4	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 0.0122% African / African-American · 7/57,197 alleles

Filtering AF 0.00567% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00406%

Overall 0.00083% 10/1,204,646 alleles · ultra-rare exomes 6/1,092,251 · genomes 4/112,395 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0122%	8,171
East Asian	0.00296%	33,766
European (non-Finnish)	0.000225%	445,030

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.Arg381His
Coding: c.1142G>A
MANE Select: NM_000444
Type: single nucleotide variant
Location: chrX:22111529 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 381: 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.Arg381Cys Conflicting classifications of pathogenicity ★ ⚠ 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
PHEX c.1174-1G>A 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-arg381his (accessed [today's date]).

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