Is PPIL4 p.Val322Ala (c.965T>C) pathogenic?

PPIL4 p.Val322Ala (c.965T>C) is classified Uncertain significance in PPIL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-18). AlphaMissense: likely pathogenic (0.8752); Very rare (popmax 0.00251%, nfe).

How common is PPIL4 p.Val322Ala (c.965T>C) in the general population?

PPIL4 p.Val322Ala (c.965T>C) is very rare (popmax 0.00251%, nfe) (gnomAD).

What do computational predictors say about PPIL4 p.Val322Ala (c.965T>C)?

AlphaMissense predicts likely pathogenic (score 0.8752) — an in-silico prediction, not a clinical call.

PPIL4 p.Val322Ala

c.965T>C · VCV3782292

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8752 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00251%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8752	likely pathogenic
REVEL	0.241	benign-leaning
SaProt	LLR -9.01	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 41 kb · p 8.5e-06 · 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 0.00251% European (non-Finnish) · 29/1,156,690 alleles

Filtering AF 0.00176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00152%

Overall 0.00189% 30/1,584,758 alleles · very rare exomes 28/1,432,780 · genomes 2/151,978 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00251%	39,886
African / African-American	0.00135%	74,004

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: PPIL4
Protein: p.Val322Ala
Coding: c.965T>C
MANE Select: NM_139126
Type: single nucleotide variant
Location: chr6:149521077 (GRCh38)
Gene constraint: LOEUF 1.088 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.56 · 7 PDB

Full PPIL4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PPIL4 p.Ala297Thr Uncertain significance ★ ⚠ same type
PPIL4 p.Arg437Gln Uncertain significance ★ ⚠ same type
PPIL4 p.Arg445Gln Uncertain significance ★ ⚠ same type
PPIL4 p.Arg476Gln Uncertain significance ★ ⚠ same type
PPIL4 p.Arg476Pro Uncertain significance ★ ⚠ same type
PPIL4 p.Arg61Cys Uncertain significance ★ ⚠ same type
PPIL4 p.Asn240Tyr Uncertain significance ★ ⚠ same type
PPIL4 p.Asn38Asp 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/ppil4-p-val322ala (accessed [today's date]).

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