Is PHEX p.Arg651Trp (c.1951C>T) pathogenic?

PHEX p.Arg651Trp (c.1951C>T) is classified Uncertain significance in PHEX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-05). AlphaMissense: likely pathogenic (0.8054); Very rare (popmax 0.00297%, eas); Associated with Inborn genetic diseases.

What condition is associated with PHEX p.Arg651Trp (c.1951C>T)?

PHEX p.Arg651Trp (c.1951C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PHEX p.Arg651Trp (c.1951C>T) in the general population?

PHEX p.Arg651Trp (c.1951C>T) is very rare (popmax 0.00297%, eas) (gnomAD).

What do computational predictors say about PHEX p.Arg651Trp (c.1951C>T)?

AlphaMissense predicts likely pathogenic (score 0.8054) — an in-silico prediction, not a clinical call.

PHEX p.Arg651Trp

c.1951C>T · VCV4135595

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8054 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00297%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8054	likely pathogenic
REVEL	0.837	moderately pathogenic-leaning
SaProt	LLR -12.31	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.5	GERP -1.2, phastCons 0.99
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	25.1	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 0.00297% East Asian · 1/33,700 alleles

Filtering AF 0.00117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000952%

Overall 0.00158% 19/1,202,416 alleles · very rare exomes 19/1,091,404 · genomes 0/111,012 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00297%	33,700
European (non-Finnish)	0.00191%	52,283
South Asian	0.00176%	56,680

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.Arg651Trp
Coding: c.1951C>T
MANE Select: NM_000444
Type: single nucleotide variant
Location: chrX:22226494 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 651: the peptidase m13 domain; a UniProt-annotated variant site (in xlhrd)

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

Similar variants

PHEX p.Arg651Pro Pathogenic ★★ same residue
PHEX p.Arg651Gln Benign ★ ⚠ same residue
PHEX p.Ala524Val Uncertain significance ★★ ⚠ same condition
PHEX p.Arg166His Uncertain significance ★★ ⚠ same condition
PHEX p.Arg443His Uncertain significance ★★ ⚠ same condition
PHEX p.Arg697Lys Uncertain significance ★★ same condition
PHEX p.Asn680Lys Uncertain significance ★★ ⚠ same condition
PHEX p.Asn718Ser Uncertain significance ★★ ⚠ 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-arg651trp (accessed [today's date]).

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