Is PRKN p.Ala46Ser (c.136G>T) pathogenic?

PRKN p.Ala46Ser (c.136G>T) is classified Uncertain significance in PRKN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-18). AlphaMissense: likely benign (0.3319); Very rare (popmax 0.00133%, afr).

How common is PRKN p.Ala46Ser (c.136G>T) in the general population?

PRKN p.Ala46Ser (c.136G>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PRKN p.Ala46Ser (c.136G>T)?

AlphaMissense predicts likely benign (score 0.3319) — an in-silico prediction, not a clinical call.

PRKN p.Ala46Ser

c.136G>T · rs75860381 · VCV958287

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3319 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.3319	likely benign
REVEL	0.513	indeterminate
SaProt	LLR -8.14	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 1,378 kb · p 0.013 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00133% African / African-American · 1/74,986 alleles

Overall 0.000186% 3/1,612,994 alleles · very rare exomes 3/1,460,782 · genomes 0/152,212 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00321%	31,201
African / African-Americangrpmax	0.00133%	74,986

Remaining individuals 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.Ala46Ser
Coding: c.136G>T
MANE Select: NM_004562
dbSNP: rs75860381
Type: single nucleotide variant
Location: chr6:162443345 (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 46: the ubiquitin-like domain; a UniProt-annotated variant site (in park2)

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

Similar variants

PRKN p.Ala46Thr Benign/Likely benign ★★ ⚠ same residue
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

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-ala46ser (accessed [today's date]).

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