Is PLPP5 p.Asp258Ala (c.773A>C) pathogenic?

PLPP5 p.Asp258Ala (c.773A>C) is classified Uncertain significance in PLPP5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-03). AlphaMissense: likely benign (0.0808); Very rare (popmax 0.00597%, sas).

How common is PLPP5 p.Asp258Ala (c.773A>C) in the general population?

PLPP5 p.Asp258Ala (c.773A>C) is very rare (popmax 0.00597%, sas) (gnomAD).

What do computational predictors say about PLPP5 p.Asp258Ala (c.773A>C)?

AlphaMissense predicts likely benign (score 0.0808) — an in-silico prediction, not a clinical call.

PLPP5 p.Asp258Ala

c.773A>C · rs762432644 · VCV2457612

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0808 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00597%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0808	likely benign
REVEL	0.061	moderately benign-leaning
SaProt	LLR -6.15	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.4	GERP -1.6
Regional constraint	o/e 0.95	unconstrained · MANE · 4,752 bp · p 0.35 · regional, not allelic
Overall
CADD	7.751	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00597% South Asian · 5/83,804 alleles

Filtering AF 0.00234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00147%

Overall 0.00207% 32/1,549,594 alleles · very rare exomes 27/1,397,530 · genomes 5/152,064 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00597%	16,761
African / African-American	0.00274%	36,453
European (non-Finnish)	0.00218%	45,862

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.Asp258Ala
Coding: c.773A>C
MANE Select: NM_001102559
dbSNP: rs762432644
Type: single nucleotide variant
Location: chr8:38264466 (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-asp258ala (accessed [today's date]).

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