Is PHLPP1 p.Arg258Pro (c.773G>C) pathogenic?

PHLPP1 p.Arg258Pro (c.773G>C) is classified Uncertain significance in PHLPP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely benign (0.0681); Very rare (popmax 0.00234%, sas).

How common is PHLPP1 p.Arg258Pro (c.773G>C) in the general population?

PHLPP1 p.Arg258Pro (c.773G>C) is very rare (popmax 0.00234%, sas) (gnomAD).

What do computational predictors say about PHLPP1 p.Arg258Pro (c.773G>C)?

AlphaMissense predicts likely benign (score 0.0681) — an in-silico prediction, not a clinical call.

PHLPP1 p.Arg258Pro

c.773G>C · VCV4567634

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0681 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00234%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0681	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -4.89	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.72	GERP -0.69
Regional constraint	o/e 1.13	unconstrained · MANE · 1,354 bp · p 0.001 · regional, not allelic
Overall
CADD	8.09	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 0.00234% South Asian · 1/42,692 alleles

Overall 7.7e-05% 1/1,297,994 alleles · very rare exomes 1/1,147,148 · genomes 0/150,846 · 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: PHLPP1
Protein: p.Arg258Pro
Coding: c.773G>C
MANE Select: NM_194449
Type: single nucleotide variant
Location: chr18:62716456 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.22 (gnomAD)
Structure: AlphaFold pLDDT 66.08
Residue 258: the 'disordered' region

Full PHLPP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PHLPP1 p.Ala876Val Uncertain significance ★★ ⚠ same type
PHLPP1 p.His197= Benign ★★ same type
PHLPP1 p.Phe291Val Benign ★★ same type
PHLPP1 p.Pro1690= Benign ★★ same type
PHLPP1 p.Ala1004Val Uncertain significance ★ ⚠ same type
PHLPP1 p.Ala107Thr Uncertain significance ★ ⚠ same type
PHLPP1 p.Ala112Val Uncertain significance ★ ⚠ same type
PHLPP1 p.Ala1167Thr Uncertain significance ★ ⚠ 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/phlpp1-p-arg258pro (accessed [today's date]).

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