Is PHEX p.His218Arg (c.653A>G) pathogenic?

PHEX p.His218Arg (c.653A>G) is classified Conflicting classifications of pathogenicity in PHEX (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-05-26). AlphaMissense: likely benign (0.3262); Rare (popmax 0.113%, sas); Associated with Inborn genetic diseases.

What condition is associated with PHEX p.His218Arg (c.653A>G)?

PHEX p.His218Arg (c.653A>G) is associated with Inborn genetic diseases, X-linked dominant hypophosphatemic rickets (ClinVar).

How common is PHEX p.His218Arg (c.653A>G) in the general population?

PHEX p.His218Arg (c.653A>G) is rare (popmax 0.113%, sas) (gnomAD).

What do computational predictors say about PHEX p.His218Arg (c.653A>G)?

AlphaMissense predicts likely benign (score 0.3262) — an in-silico prediction, not a clinical call.

PHEX p.His218Arg

c.653A>G · rs774907553 · VCV913064

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.3262 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.113%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3262	likely benign
REVEL	0.366	indeterminate
SaProt	LLR -9.76	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	20.4	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 0.113% South Asian · 64/56,484 alleles

Filtering AF 0.091% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.083%

Overall 0.00553% 66/1,193,886 alleles · rare exomes 63/1,081,693 · genomes 3/112,193 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.113%	883
Remaining individualsnot grpmax-eligible	0.00212%	47,110
European (non-Finnish)	0.000114%	880,235

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.His218Arg
Coding: c.653A>G
MANE Select: NM_000444
dbSNP: rs774907553
Type: single nucleotide variant
Location: chrX:22077692 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 218: 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 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-his218arg (accessed [today's date]).

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