Is PHLPP2 p.Leu367Val (c.1099C>G) pathogenic?

PHLPP2 p.Leu367Val (c.1099C>G) is classified Uncertain significance in PHLPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-28). AlphaMissense: likely benign (0.2666); Very rare (popmax 0.000509%, nfe).

How common is PHLPP2 p.Leu367Val (c.1099C>G) in the general population?

PHLPP2 p.Leu367Val (c.1099C>G) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about PHLPP2 p.Leu367Val (c.1099C>G)?

AlphaMissense predicts likely benign (score 0.2666) — an in-silico prediction, not a clinical call.

PHLPP2 p.Leu367Val

c.1099C>G · rs1333557875 · VCV3212358

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2666 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2666	likely benign
REVEL	0.292	indeterminate
SaProt	LLR -12.97	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 2.1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 66 kb · p 0.034 · regional, not allelic
Overall
CADD	24.8	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 0.000509% European (non-Finnish) · 6/1,179,414 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,220 alleles · very rare exomes 5/1,461,062 · genomes 1/152,158 · 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.Leu367Val
Coding: c.1099C>G
MANE Select: NM_015020
dbSNP: rs1333557875
Type: single nucleotide variant
Location: chr16:71678924 (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-leu367val (accessed [today's date]).

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