Is PHEX p.Arg381Cys (c.1141C>T) pathogenic?

PHEX p.Arg381Cys (c.1141C>T) is classified Conflicting classifications of pathogenicity in PHEX (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-31). AlphaMissense: likely pathogenic (0.7953); Ultra-rare (popmax 0.0131%, amr); Associated with Inborn genetic diseases.

What condition is associated with PHEX p.Arg381Cys (c.1141C>T)?

PHEX p.Arg381Cys (c.1141C>T) is associated with Inborn genetic diseases, X-linked dominant hypophosphatemic rickets (ClinVar).

How common is PHEX p.Arg381Cys (c.1141C>T) in the general population?

PHEX p.Arg381Cys (c.1141C>T) is ultra-rare (popmax 0.0131%, amr) (gnomAD).

What do computational predictors say about PHEX p.Arg381Cys (c.1141C>T)?

AlphaMissense predicts likely pathogenic (score 0.7953) — an in-silico prediction, not a clinical call.

PHEX p.Arg381Cys

c.1141C>T · rs932260939 · VCV1544435

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7953 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0131%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7953	likely pathogenic
REVEL	0.844	moderately pathogenic-leaning
SaProt	LLR -11.54	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	29.3	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 0.0131% Admixed American · 6/45,778 alleles

Filtering AF 0.00569% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00388%

Overall 0.00232% 28/1,204,668 alleles · ultra-rare exomes 21/1,092,312 · genomes 7/112,356 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0131%	7,630
East Asian	0.00889%	11,252
Remaining individualsnot grpmax-eligible	0.00211%	47,441
European (non-Finnish)	0.00191%	52,357
South Asian	0.00176%	56,748

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.Arg381Cys
Coding: c.1141C>T
MANE Select: NM_000444
dbSNP: rs932260939
Type: single nucleotide variant
Location: chrX:22111528 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: X-linked dominant hypophosphatemic rickets

Similar variants

PHEX p.Arg381His 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
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-arg381cys (accessed [today's date]).

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