Is PHEX p.Leu438Ser (c.1313T>C) pathogenic?

PHEX p.Leu438Ser (c.1313T>C) is classified Conflicting classifications of pathogenicity in PHEX (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-01-28). AlphaMissense: likely pathogenic (0.9671); Absent from gnomAD v4.1.

How common is PHEX p.Leu438Ser (c.1313T>C) in the general population?

PHEX p.Leu438Ser (c.1313T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PHEX p.Leu438Ser (c.1313T>C)?

AlphaMissense predicts likely pathogenic (score 0.9671) — an in-silico prediction, not a clinical call.

PHEX p.Leu438Ser

c.1313T>C · rs1057517904 · VCV372646

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9671 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9671	likely pathogenic
REVEL	0.808	moderately pathogenic-leaning
SaProt	LLR -13.28	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	23.2	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.Leu438Ser
Coding: c.1313T>C
MANE Select: NM_000444
dbSNP: rs1057517904
Type: single nucleotide variant
Location: chrX:22133533 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 438: the peptidase m13 domain

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

Similar variants

PHEX p.Leu438Ter Pathogenic ★ same residue
PHEX p.Leu438fs 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

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-leu438ser (accessed [today's date]).

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