Is PHEX p.Val407Ala (c.1220T>C) pathogenic?

PHEX p.Val407Ala (c.1220T>C) is classified Uncertain significance in PHEX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-14). AlphaMissense: ambiguous (0.5529); Very rare (popmax 0.000341%, nfe).

How common is PHEX p.Val407Ala (c.1220T>C) in the general population?

PHEX p.Val407Ala (c.1220T>C) is very rare (popmax 0.000341%, nfe) (gnomAD).

What do computational predictors say about PHEX p.Val407Ala (c.1220T>C)?

AlphaMissense predicts ambiguous (score 0.5529) — an in-silico prediction, not a clinical call.

PHEX p.Val407Ala

c.1220T>C · VCV4717186

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5529 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000341%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5529	ambiguous
REVEL	0.549	indeterminate
SaProt	LLR -9.24	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	23.1	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 0.000341% European (non-Finnish) · 3/879,764 alleles

Filtering AF 9.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000251% 3/1,192,965 alleles · very rare exomes 2/1,081,201 · genomes 1/111,764 · 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.Val407Ala
Coding: c.1220T>C
MANE Select: NM_000444
Type: single nucleotide variant
Location: chrX:22114504 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 407: the peptidase m13 domain

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

Similar variants

PHEX p.Val407Gly Uncertain significance ★ ⚠ same residue
PHEX p.Val407Ile Uncertain significance ★ ⚠ 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-val407ala (accessed [today's date]).

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