Is PHLPP2 p.Pro731Ala (c.2191C>G) pathogenic?

PHLPP2 p.Pro731Ala (c.2191C>G) is classified Uncertain significance in PHLPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely benign (0.332); Ultra-rare (popmax 0.0567%, amr).

How common is PHLPP2 p.Pro731Ala (c.2191C>G) in the general population?

PHLPP2 p.Pro731Ala (c.2191C>G) is ultra-rare (popmax 0.0567%, amr) (gnomAD).

What do computational predictors say about PHLPP2 p.Pro731Ala (c.2191C>G)?

AlphaMissense predicts likely benign (score 0.332) — an in-silico prediction, not a clinical call.

PHLPP2 p.Pro731Ala

c.2191C>G · VCV4136032

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.332 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0567%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.332	likely benign
REVEL	0.114	moderately benign-leaning
SaProt	LLR -11.62	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 66 kb · p 0.034 · regional, not allelic
Overall
CADD	24.0	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

Grpmax group 0.0567% Admixed American · 34/59,994 alleles

Filtering AF 0.0416% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0365%

Overall 0.00266% 43/1,613,694 alleles · ultra-rare exomes 16/1,461,416 · genomes 27/152,278 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0567%	1,765
Remaining individualsnot grpmax-eligible	0.0096%	10,416
African / African-American	0.00133%	75,030
European (non-Finnish)	0.00017%	589,849

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.Pro731Ala
Coding: c.2191C>G
MANE Select: NM_015020
Type: single nucleotide variant
Location: chr16:71658321 (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-pro731ala (accessed [today's date]).

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