Is PHEX p.Ala689Val (c.2066C>T) pathogenic?

PHEX p.Ala689Val (c.2066C>T) is classified Likely pathogenic in PHEX (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-08-14). AlphaMissense: likely pathogenic (0.8442); Absent from gnomAD v4.1; Associated with PHEX-related disorder.

What condition is associated with PHEX p.Ala689Val (c.2066C>T)?

PHEX p.Ala689Val (c.2066C>T) is associated with PHEX-related disorder (ClinVar).

How common is PHEX p.Ala689Val (c.2066C>T) in the general population?

PHEX p.Ala689Val (c.2066C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PHEX p.Ala689Val (c.2066C>T)?

AlphaMissense predicts likely pathogenic (score 0.8442) — an in-silico prediction, not a clinical call.

PHEX p.Ala689Val

c.2066C>T · VCV3344649

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8442 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PHEX-related disorder

Computational evidence

Protein change
AlphaMissense	0.8442	likely pathogenic ✓ concordant with ClinVar
REVEL	0.923	moderately pathogenic-leaning
SaProt	LLR -12.15	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 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	25.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PHEX
Protein: p.Ala689Val
Coding: c.2066C>T
MANE Select: NM_000444
Type: single nucleotide variant
Location: chrX:22227607 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 689: the peptidase m13 domain

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

Disease context

PHEX-related disorder

Similar variants

PHEX p.Ala689Pro Likely pathogenic ★ same residue
PHEX p.Ala689Gly Uncertain significance ★ ⚠ same residue
PHEX c.118+1G>A Pathogenic/Likely pathogenic ★★ same condition
PHEX c.1302+1G>A Pathogenic ★★ same condition
PHEX c.1482+2T>A Pathogenic/Likely pathogenic ★★ same condition
PHEX c.1587-1G>A Pathogenic ★★ same condition
PHEX c.1645+1G>A Pathogenic/Likely pathogenic ★★ same condition
PHEX c.732+1G>A Pathogenic/Likely 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-ala689val (accessed [today's date]).

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