Is PLPP5 p.Ser154Cys (c.461C>G) pathogenic?

PLPP5 p.Ser154Cys (c.461C>G) is classified Uncertain significance in PLPP5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-02). AlphaMissense: likely pathogenic (0.7642); Ultra-rare (popmax 0.0681%, afr).

How common is PLPP5 p.Ser154Cys (c.461C>G) in the general population?

PLPP5 p.Ser154Cys (c.461C>G) is ultra-rare (popmax 0.0681%, afr) (gnomAD).

What do computational predictors say about PLPP5 p.Ser154Cys (c.461C>G)?

AlphaMissense predicts likely pathogenic (score 0.7642) — an in-silico prediction, not a clinical call.

PLPP5 p.Ser154Cys

c.461C>G · VCV4569608

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7642 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0681%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7642	likely pathogenic
REVEL	0.907	moderately pathogenic-leaning
SaProt	LLR -14.83	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 4,752 bp · p 0.35 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0681% African / African-American · 51/74,886 alleles

Filtering AF 0.0532% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0479%

Overall 0.00328% 53/1,613,828 alleles · ultra-rare exomes 33/1,461,686 · genomes 20/152,142 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0681%	1,468
Remaining individualsnot grpmax-eligible	0.0032%	31,231

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: PLPP5
Protein: p.Ser154Cys
Coding: c.461C>G
MANE Select: NM_001102559
Type: single nucleotide variant
Location: chr8:38267269 (GRCh38)
Gene constraint: LOEUF 1.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.84

Full PLPP5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLPP5 p.Ala156Pro Uncertain significance ★ ⚠ same type
PLPP5 p.Ala22Val Uncertain significance ★ ⚠ same type
PLPP5 p.Ala4Glu Uncertain significance ★ ⚠ same type
PLPP5 p.Ala5Val Uncertain significance ★ ⚠ same type
PLPP5 p.Ala96Pro Uncertain significance ★ ⚠ same type
PLPP5 p.Ala98Thr Uncertain significance ★ ⚠ same type
PLPP5 p.Arg115Gly Uncertain significance ★ ⚠ same type
PLPP5 p.Arg121Leu 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/plpp5-p-ser154cys (accessed [today's date]).

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