Is PHEX p.Arg127Trp (c.379C>T) pathogenic?

PHEX p.Arg127Trp (c.379C>T) is classified Benign in PHEX (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-30). AlphaMissense: likely benign (0.163); Very rare (popmax 0.00964%, nfe).

How common is PHEX p.Arg127Trp (c.379C>T) in the general population?

PHEX p.Arg127Trp (c.379C>T) is very rare (popmax 0.00964%, nfe) (gnomAD).

What do computational predictors say about PHEX p.Arg127Trp (c.379C>T)?

AlphaMissense predicts likely benign (score 0.163) — an in-silico prediction, not a clinical call.

PHEX p.Arg127Trp

c.379C>T · rs375376231 · VCV1651244

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.163 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00964%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.163	likely benign
REVEL	0.421	indeterminate
SaProt	LLR -10.39	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.1	GERP -0.32, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	23.0	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 0.00964% European (non-Finnish) · 86/892,182 alleles

Filtering AF 0.00799% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00736%

Overall 0.00771% 93/1,206,787 alleles · very rare exomes 89/1,094,689 · genomes 4/112,098 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00964%	10,374
Admixed American	0.00655%	15,261
South Asian	0.00352%	28,380
Remaining individualsnot grpmax-eligible	0.00211%	47,495
African / African-American	0.00175%	57,174

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.Arg127Trp
Coding: c.379C>T
MANE Select: NM_000444
dbSNP: rs375376231
Type: single nucleotide variant
Location: chrX:22076417 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 127: the peptidase m13 domain

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

Similar variants

PHEX p.Arg127Gln Benign/Likely benign ★★ 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
PHEX c.1173+2T>C 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-arg127trp (accessed [today's date]).

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