Is PLPP5 p.Ala4Glu (c.11C>A) pathogenic?

PLPP5 p.Ala4Glu (c.11C>A) is classified Uncertain significance in PLPP5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely benign (0.1201); Ultra-rare (popmax 0.035%, nfe).

How common is PLPP5 p.Ala4Glu (c.11C>A) in the general population?

PLPP5 p.Ala4Glu (c.11C>A) is ultra-rare (popmax 0.035%, nfe) (gnomAD).

What do computational predictors say about PLPP5 p.Ala4Glu (c.11C>A)?

AlphaMissense predicts likely benign (score 0.1201) — an in-silico prediction, not a clinical call.

PLPP5 p.Ala4Glu

c.11C>A · VCV4139907

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1201 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.035%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1201	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -7.22	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 -2.5	GERP -2.9
Regional constraint	o/e 0.95	unconstrained · MANE · 4,752 bp · p 0.35 · regional, not allelic
Overall
CADD	12.01	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 0.035% European (non-Finnish) · 397/1,133,286 alleles

Filtering AF 0.0321% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.031%

Overall 0.0289% 434/1,501,660 alleles · ultra-rare exomes 406/1,349,450 · genomes 28/152,210 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0365%	2,740
European (non-Finnish)grpmax	0.035%	2,855
Remaining individualsnot grpmax-eligible	0.0274%	3,645
African / African-American	0.00581%	17,201
Admixed American	0.00212%	47,242

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala4Glu
Coding: c.11C>A
MANE Select: NM_001102559
Type: single nucleotide variant
Location: chr8:38269189 (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.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
PLPP5 p.Arg179His 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-ala4glu (accessed [today's date]).

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