Is PPIL4 p.Asp232His (c.694G>C) pathogenic?

PPIL4 p.Asp232His (c.694G>C) is classified Uncertain significance in PPIL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-12). AlphaMissense: likely pathogenic (0.6287); Ultra-rare (popmax 0.0167%, amr).

How common is PPIL4 p.Asp232His (c.694G>C) in the general population?

PPIL4 p.Asp232His (c.694G>C) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about PPIL4 p.Asp232His (c.694G>C)?

AlphaMissense predicts likely pathogenic (score 0.6287) — an in-silico prediction, not a clinical call.

PPIL4 p.Asp232His

c.694G>C · VCV4142465

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6287 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6287	likely pathogenic
REVEL	0.583	indeterminate
SaProt	LLR -11.31	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 41 kb · p 8.5e-06 · regional, not allelic
Overall
CADD	29.0	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 0.0167% Admixed American · 10/59,878 alleles

Filtering AF 0.00901% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00683%

Overall 0.00248% 40/1,612,616 alleles · ultra-rare exomes 33/1,460,424 · genomes 7/152,192 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,988
Remaining individualsnot grpmax-eligible	0.0032%	31,214
European (non-Finnish)	0.00237%	42,120

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.Asp232His
Coding: c.694G>C
MANE Select: NM_139126
Type: single nucleotide variant
Location: chr6:149526761 (GRCh38)
Gene constraint: LOEUF 1.088 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.56 · 7 PDB
Residue 232: a β-strand

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

Similar variants

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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-asp232his (accessed [today's date]).

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