Is PRKN p.Ser296Phe (c.887C>T) pathogenic?

PRKN p.Ser296Phe (c.887C>T) is classified Uncertain significance in PRKN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-16). AlphaMissense: likely pathogenic (0.8925); Very rare (popmax 0.00017%, nfe).

How common is PRKN p.Ser296Phe (c.887C>T) in the general population?

PRKN p.Ser296Phe (c.887C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about PRKN p.Ser296Phe (c.887C>T)?

AlphaMissense predicts likely pathogenic (score 0.8925) — an in-silico prediction, not a clinical call.

PRKN p.Ser296Phe

c.887C>T · rs1257682809 · VCV1976035

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8925 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8925	likely pathogenic
REVEL	0.805	moderately pathogenic-leaning
SaProt	LLR -12.26	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 1,378 kb · p 0.013 · regional, not allelic
Overall
CADD	30.0	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 0.00017% European (non-Finnish) · 2/1,179,800 alleles

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

Overall 0.000186% 3/1,613,906 alleles · very rare exomes 3/1,461,568 · genomes 0/152,338 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,022
European (non-Finnish)grpmax	0.00017%	589,901

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: PRKN
Protein: p.Ser296Phe
Coding: c.887C>T
MANE Select: NM_004562
dbSNP: rs1257682809
Type: single nucleotide variant
Location: chr6:161569401 (GRCh38)
Gene constraint: LOEUF 1.17 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 79.10 · 21 PDB
Residue 296: the 'triad supradomain' region

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

Similar variants

PRKN p.Arg275Trp Pathogenic/Likely pathogenic ★★ same type
PRKN p.Arg33Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
PRKN p.Arg33Ter Pathogenic ★★ same type
PRKN p.Arg42Pro Pathogenic ★★ same type
PRKN p.Cys212Tyr Pathogenic ★★ same type
PRKN p.Cys253Tyr Pathogenic/Likely pathogenic ★★ same type
PRKN p.Cys268Ter Pathogenic ★★ same type
PRKN p.Cys441Arg 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/prkn-p-ser296phe (accessed [today's date]).

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