Is PHEX p.Ala552Val (c.1655C>T) pathogenic?

PHEX p.Ala552Val (c.1655C>T) is classified Uncertain significance in PHEX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-29). AlphaMissense: likely pathogenic (0.8104); Ultra-rare (popmax 0.0175%, amr); Associated with X-linked dominant hypophosphatemic rickets.

What condition is associated with PHEX p.Ala552Val (c.1655C>T)?

PHEX p.Ala552Val (c.1655C>T) is associated with X-linked dominant hypophosphatemic rickets (ClinVar).

How common is PHEX p.Ala552Val (c.1655C>T) in the general population?

PHEX p.Ala552Val (c.1655C>T) is ultra-rare (popmax 0.0175%, amr) (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.Ala552Val (c.1655C>T)?

AlphaMissense predicts likely pathogenic (score 0.8104) — an in-silico prediction, not a clinical call.

PHEX p.Ala552Val

c.1655C>T · rs773244112 · VCV368169

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8104 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0175%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked dominant hypophosphatemic rickets

Computational evidence

Protein change
AlphaMissense	0.8104	likely pathogenic
REVEL	0.883	moderately pathogenic-leaning
SaProt	LLR -10.02	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 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0175% Admixed American · 8/45,700 alleles

Filtering AF 0.0087% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00631%

Overall 0.000916% 11/1,201,205 alleles · ultra-rare exomes 9/1,089,562 · genomes 2/111,643 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0175%	5,712
European (non-Finnish)	0.000338%	295,810

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.Ala552Val
Coding: c.1655C>T
MANE Select: NM_000444
dbSNP: rs773244112
Type: single nucleotide variant
Location: chrX:22212913 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 552: 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.Ala552= Likely benign ★ 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-ala552val (accessed [today's date]).

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