Is PINK1 p.Pro399Ser (c.1195C>T) pathogenic?

PINK1 p.Pro399Ser (c.1195C>T) is classified Uncertain significance in PINK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-02-13). AlphaMissense: likely benign (0.2656); Very rare (popmax 0.000169%, nfe).

How common is PINK1 p.Pro399Ser (c.1195C>T) in the general population?

PINK1 p.Pro399Ser (c.1195C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about PINK1 p.Pro399Ser (c.1195C>T)?

AlphaMissense predicts likely benign (score 0.2656) — an in-silico prediction, not a clinical call.

PINK1 p.Pro399Ser

c.1195C>T · VCV4960039

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2656 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2656	likely benign
REVEL	0.338	indeterminate
SaProt	LLR -10.31	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; 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 0.96	unconstrained · MANE · 17 kb · p 0.24 · regional, not allelic
Overall
CADD	28.2	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 0.000169% European (non-Finnish) · 2/1,180,028 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,132 alleles · very rare exomes 2/1,461,852 · genomes 0/152,280 · joint denominator

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: PINK1
Protein: p.Pro399Ser
Coding: c.1195C>T
MANE Select: NM_032409
Type: single nucleotide variant
Location: chr1:20648576 (GRCh38)
Gene constraint: LOEUF 1.314 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.82 · 6 PDB
Residue 399: a β-strand; the protein kinase domain; a UniProt-annotated variant site (found in early-onset parkinson disease with digenic inheritance; likely pathogenic; the patient also has mutation s-39 in park7; decreases prkn and sncaip ubiquitination and degradation)

Full PINK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PINK1 p.Pro399Leu Uncertain significance ★ ⚠ same residue
PINK1 c.1252-1G>A Pathogenic/Likely pathogenic ★★ same type
PINK1 c.960-2A>G Likely pathogenic ★★ same type
PINK1 p.Arg492Ter Pathogenic ★★ same type
PINK1 p.Arg501Ter Pathogenic/Likely pathogenic ★★ same type
PINK1 p.Gln456Ter Pathogenic ★★ same type
PINK1 p.Leu347Pro Pathogenic ★★ same type
PINK1 p.Thr313Met Pathogenic/Likely pathogenic ★★ 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/pink1-p-pro399ser (accessed [today's date]).

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