Is PHLPP2 p.Cys258Phe (c.773G>T) pathogenic?

PHLPP2 p.Cys258Phe (c.773G>T) is classified Uncertain significance in PHLPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-14). AlphaMissense: ambiguous (0.4482); Absent from gnomAD v4.1.

How common is PHLPP2 p.Cys258Phe (c.773G>T) in the general population?

PHLPP2 p.Cys258Phe (c.773G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PHLPP2 p.Cys258Phe (c.773G>T)?

AlphaMissense predicts ambiguous (score 0.4482) — an in-silico prediction, not a clinical call.

PHLPP2 p.Cys258Phe

c.773G>T · rs2479340612 · VCV3212378

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4482 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.4482	ambiguous
REVEL	0.478	indeterminate
SaProt	LLR -1.74	tolerated
Splicing
SpliceAI	Δ0.43	acceptor gain · deltas
Pangolin	Δ0.27	gain · loss 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 66 kb · p 0.034 · regional, not allelic
Overall
CADD	33.0	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: PHLPP2
Protein: p.Cys258Phe
Coding: c.773G>T
MANE Select: NM_015020
dbSNP: rs2479340612
Type: single nucleotide variant
Location: chr16:71681868 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.11

Full PHLPP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PHLPP2 p.Asp453Gly Uncertain significance ★★ ⚠ same type
PHLPP2 p.Ile204Val Likely benign ★★ same type
PHLPP2 p.Ser1139Cys Likely benign ★★ same type
PHLPP2 p.Ala1008Thr Uncertain significance ★ ⚠ same type
PHLPP2 p.Ala1008Val Uncertain significance ★ ⚠ same type
PHLPP2 p.Ala1270Ser Uncertain significance ★ ⚠ same type
PHLPP2 p.Ala1322Val Uncertain significance ★ ⚠ same type
PHLPP2 p.Ala223Pro 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/phlpp2-p-cys258phe (accessed [today's date]).

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