Is PHEX p.Val576Ile (c.1726G>A) pathogenic?

PHEX p.Val576Ile (c.1726G>A) is classified Uncertain significance in PHEX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-28). AlphaMissense: likely benign (0.1903); Very rare (popmax 0.00177%, sas).

How common is PHEX p.Val576Ile (c.1726G>A) in the general population?

PHEX p.Val576Ile (c.1726G>A) is very rare (popmax 0.00177%, sas) (gnomAD).

What do computational predictors say about PHEX p.Val576Ile (c.1726G>A)?

AlphaMissense predicts likely benign (score 0.1903) — an in-silico prediction, not a clinical call.

PHEX p.Val576Ile

c.1726G>A · rs747692520 · VCV1719557

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1903 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00177%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1903	likely benign
REVEL	0.567	indeterminate
SaProt	LLR -8.87	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00177% South Asian · 1/56,344 alleles

Overall 8.44e-05% 1/1,184,965 alleles · very rare exomes 1/1,071,096 · genomes 0/113,869 · joint denominator

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.Val576Ile
Coding: c.1726G>A
MANE Select: NM_000444
dbSNP: rs747692520
Type: single nucleotide variant
Location: chrX:22219061 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 576: the peptidase m13 domain

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

Similar variants

PHEX p.Val576_His580delinsAsp Pathogenic ★★ 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-val576ile (accessed [today's date]).

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