Is PPIL1 p.Pro164Ser (c.490C>T) pathogenic?

PPIL1 p.Pro164Ser (c.490C>T) is classified Uncertain significance in PPIL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: ambiguous (0.3811); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with PPIL1 p.Pro164Ser (c.490C>T)?

PPIL1 p.Pro164Ser (c.490C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PPIL1 p.Pro164Ser (c.490C>T) in the general population?

PPIL1 p.Pro164Ser (c.490C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about PPIL1 p.Pro164Ser (c.490C>T)?

AlphaMissense predicts ambiguous (score 0.3811) — an in-silico prediction, not a clinical call.

PPIL1 p.Pro164Ser

c.490C>T · VCV4142436

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3811 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3811	ambiguous
REVEL	0.023	moderately benign-leaning
SaProt	LLR -7.49	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 19 kb · p 0.078 · regional, not allelic
Overall
CADD	25.0	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 0.00333% Admixed American · 2/60,004 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000248% 4/1,613,986 alleles · very rare exomes 3/1,461,844 · genomes 1/152,142 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,002
European (non-Finnish)	0.000169%	590,005

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: PPIL1
Protein: p.Pro164Ser
Coding: c.490C>T
MANE Select: NM_016059
Type: single nucleotide variant
Location: chr6:36855824 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.06 · 32 PDB
Residue 164: the ppiase cyclophilin-type domain; a UniProt-annotated variant site (in pch14); a β-strand

Full PPIL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PPIL1 p.Arg141Cys Uncertain significance ★ ⚠ same condition
PPIL1 p.Arg44Cys Uncertain significance ★ ⚠ same condition
PPIL1 p.Arg44Leu Uncertain significance ★ ⚠ same condition
PPIL1 p.Asn102Ile Uncertain significance ★ ⚠ same condition
PPIL1 p.Asn102Tyr Uncertain significance ★ ⚠ same condition
PPIL1 p.Asp123Glu Uncertain significance ★ ⚠ same condition
PPIL1 p.Asp66Tyr Uncertain significance ★ ⚠ same condition
PPIL1 p.Gly166Arg Uncertain significance ★ ⚠ same condition

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/ppil1-p-pro164ser (accessed [today's date]).

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