Is PHEX p.Arg342Cys (c.1024C>T) pathogenic?

PHEX p.Arg342Cys (c.1024C>T) is classified Likely benign in PHEX (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-04). AlphaMissense: likely pathogenic (0.8255); Ultra-rare (popmax 0.0119%, eas).

How common is PHEX p.Arg342Cys (c.1024C>T) in the general population?

PHEX p.Arg342Cys (c.1024C>T) is ultra-rare (popmax 0.0119%, eas) (gnomAD).

What do computational predictors say about PHEX p.Arg342Cys (c.1024C>T)?

AlphaMissense predicts likely pathogenic (score 0.8255) — an in-silico prediction, not a clinical call.

PHEX p.Arg342Cys

c.1024C>T · rs761575825 · VCV756029

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8255 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0119%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8255	likely pathogenic
REVEL	0.591	indeterminate
SaProt	LLR -7.60	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	25.0	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 0.0119% East Asian · 4/33,718 alleles

Filtering AF 0.00396% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00149% 18/1,205,623 alleles · ultra-rare exomes 13/1,094,991 · genomes 5/110,632 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0119%	8,429
Admixed American	0.00659%	15,183
South Asian	0.00353%	28,325
Finnishnot grpmax-eligible	0.00216%	46,359
European (non-Finnish)	0.000897%	111,514

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.Arg342Cys
Coding: c.1024C>T
MANE Select: NM_000444
dbSNP: rs761575825
Type: single nucleotide variant
Location: chrX:22099096 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 342: the peptidase m13 domain

Full PHEX gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PHEX p.Arg342= Conflicting classifications of pathogenicity ★ same residue
PHEX p.Arg342His Conflicting classifications of pathogenicity ★ ⚠ same residue
PHEX c.1079+1G>A Pathogenic ★★ same type
PHEX c.1079+2T>G Pathogenic ★★ same type
PHEX c.1080-1G>A Pathogenic ★★ same type
PHEX c.1080-2A>G Pathogenic ★★ same type
PHEX c.1080-3C>G Pathogenic ★★ same type
PHEX c.1173+1G>A Pathogenic ★★ same type

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-arg342cys (accessed [today's date]).

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