Is PHLPP2 p.Ala223Pro (c.667G>C) pathogenic?

PHLPP2 p.Ala223Pro (c.667G>C) is classified Uncertain significance in PHLPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-13). AlphaMissense: ambiguous (0.4989); Very rare (popmax 8.47e-05%, nfe).

How common is PHLPP2 p.Ala223Pro (c.667G>C) in the general population?

PHLPP2 p.Ala223Pro (c.667G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about PHLPP2 p.Ala223Pro (c.667G>C)?

AlphaMissense predicts ambiguous (score 0.4989) — an in-silico prediction, not a clinical call.

PHLPP2 p.Ala223Pro

c.667G>C · rs996692240 · VCV2290491

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4989 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4989	ambiguous
REVEL	0.228	benign-leaning
SaProt	LLR -7.74	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 66 kb · p 0.034 · regional, not allelic
Overall
CADD	24.2	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,954 alleles

Overall 6.2e-05% 1/1,613,920 alleles · very rare exomes 1/1,461,802 · genomes 0/152,118 · 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: PHLPP2
Protein: p.Ala223Pro
Coding: c.667G>C
MANE Select: NM_015020
dbSNP: rs996692240
Type: single nucleotide variant
Location: chr16:71684544 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.11
Residue 223: the ph domain

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.Ala581Thr 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-ala223pro (accessed [today's date]).

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