Is PHEX p.Ser412Arg (c.1236T>A) pathogenic?

PHEX p.Ser412Arg (c.1236T>A) is classified Uncertain significance in PHEX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-20). AlphaMissense: likely pathogenic (0.6952); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PHEX p.Ser412Arg (c.1236T>A)?

PHEX p.Ser412Arg (c.1236T>A) is associated with Inborn genetic diseases (ClinVar).

How common is PHEX p.Ser412Arg (c.1236T>A) in the general population?

PHEX p.Ser412Arg (c.1236T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PHEX p.Ser412Arg (c.1236T>A)?

AlphaMissense predicts likely pathogenic (score 0.6952) — an in-silico prediction, not a clinical call.

PHEX p.Ser412Arg

c.1236T>A · VCV3931459

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6952 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6952	likely pathogenic
REVEL	0.352	indeterminate
SaProt	LLR -7.94	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.069	GERP -1.1, phastCons 0.89
Regional constraint	o/e 0.83	unconstrained · MANE · 215 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	16.18	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.Ser412Arg
Coding: c.1236T>A
MANE Select: NM_000444
Type: single nucleotide variant
Location: chrX:22114520 (GRCh38)
Structure: AlphaFold pLDDT 94.58
Residue 412: the peptidase m13 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PHEX p.Ala524Val Uncertain significance ★★ ⚠ same condition
PHEX p.Arg166His Uncertain significance ★★ ⚠ same condition
PHEX p.Arg443His Uncertain significance ★★ ⚠ same condition
PHEX p.Arg651Trp Uncertain significance ★★ ⚠ same condition
PHEX p.Arg697Lys Uncertain significance ★★ same condition
PHEX p.Asn680Lys Uncertain significance ★★ ⚠ same condition
PHEX p.Asn718Ser Uncertain significance ★★ ⚠ same condition
PHEX p.Asp501Tyr Uncertain significance ★★ ⚠ 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-ser412arg (accessed [today's date]).

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