Is PPP5C p.Val445Ile (c.1333G>A) pathogenic?

PPP5C p.Val445Ile (c.1333G>A) is classified Uncertain significance in PPP5C (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-06). AlphaMissense: likely benign (0.0854); Very rare (popmax 0.00322%, nfe).

How common is PPP5C p.Val445Ile (c.1333G>A) in the general population?

PPP5C p.Val445Ile (c.1333G>A) is very rare (popmax 0.00322%, nfe) (gnomAD).

What do computational predictors say about PPP5C p.Val445Ile (c.1333G>A)?

AlphaMissense predicts likely benign (score 0.0854) — an in-silico prediction, not a clinical call.

PPP5C p.Val445Ile

c.1333G>A · VCV3309555

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0854 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00322%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0854	likely benign
REVEL	0.162	moderately benign-leaning
SaProt	LLR -8.31	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 10	GERP 1.4, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 43 kb · p 1.3e-21 · regional, not allelic
Overall
CADD	24.6	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 0.00322% European (non-Finnish) · 38/1,180,014 alleles

Filtering AF 0.00239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.0026% 42/1,614,012 alleles · very rare exomes 38/1,461,830 · genomes 4/152,182 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00322%	31,053
East Asian	0.00223%	44,888
Remaining individualsnot grpmax-eligible	0.0016%	62,490
Finnishnot grpmax-eligible	0.00156%	64,012
South Asian	0.0011%	91,080

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: PPP5C
Protein: p.Val445Ile
Coding: c.1333G>A
MANE Select: NM_006247
Type: single nucleotide variant
Location: chr19:46388709 (GRCh38)
Gene constraint: LOEUF 0.456 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 93.00 · 22 PDB
Residue 445: the 'catalytic' region; a β-strand

Full PPP5C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PPP5C p.Ala115Thr Uncertain significance ★ ⚠ same type
PPP5C p.Ala153Gly Uncertain significance ★ ⚠ same type
PPP5C p.Ala325Val Uncertain significance ★ ⚠ same type
PPP5C p.Ala54Ser Uncertain significance ★ ⚠ same type
PPP5C p.Ala62Thr Uncertain significance ★ ⚠ same type
PPP5C p.Arg150Trp Uncertain significance ★ ⚠ same type
PPP5C p.Arg159His Uncertain significance ★ ⚠ same type
PPP5C p.Arg275Gln 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/ppp5c-p-val445ile (accessed [today's date]).

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