Is PRSS56 p.Pro466Arg (c.1397C>G) pathogenic?

PRSS56 p.Pro466Arg (c.1397C>G) is classified Uncertain significance in PRSS56 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). AlphaMissense: likely benign (0.0562); Very rare (popmax 8.72e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PRSS56 p.Pro466Arg (c.1397C>G)?

PRSS56 p.Pro466Arg (c.1397C>G) is associated with Inborn genetic diseases (ClinVar).

How common is PRSS56 p.Pro466Arg (c.1397C>G) in the general population?

PRSS56 p.Pro466Arg (c.1397C>G) is very rare (popmax 8.72e-05%, nfe) (gnomAD).

What do computational predictors say about PRSS56 p.Pro466Arg (c.1397C>G)?

AlphaMissense predicts likely benign (score 0.0562) — an in-silico prediction, not a clinical call.

PRSS56 p.Pro466Arg

c.1397C>G · rs1444165409 · VCV3219933

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0562 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.72e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0562	likely benign
SaProt	LLR -6.93	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP -3
Regional constraint	o/e 1.09	unconstrained · MANE · 2,443 bp · p 0.05 · regional, not allelic
Overall
CADD	0.177	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; SaProt is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.72e-05% European (non-Finnish) · 1/1,146,724 alleles

Overall 6.51e-05% 1/1,535,540 alleles · very rare exomes 1/1,383,190 · genomes 0/152,350 · 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: PRSS56
Protein: p.Pro466Arg
Coding: c.1397C>G
MANE Select: NM_001195129
dbSNP: rs1444165409
Type: single nucleotide variant
Location: chr2:232524352 (GRCh38)
Gene constraint: LOEUF 1.11 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.35
Residue 466: the 'disordered' region

Full PRSS56 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

PRSS56 p.Pro466Ala Uncertain significance ★ ⚠ same residue
PRSS56 p.Pro466Thr Uncertain significance ★ ⚠ same residue
PRSS56 p.Ala502Thr Uncertain significance ★★ ⚠ same condition
PRSS56 p.Asp254Asn Uncertain significance ★★ ⚠ same condition
PRSS56 p.Asp285Asn Uncertain significance ★★ ⚠ same condition
PRSS56 p.Gly538Ser Uncertain significance ★★ ⚠ same condition
PRSS56 p.Leu483Phe Uncertain significance ★★ ⚠ same condition
PRSS56 p.Pro354Ala 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/prss56-p-pro466arg (accessed [today's date]).

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