Is PRSS56 p.Pro299Arg (c.896C>G) pathogenic?

PRSS56 p.Pro299Arg (c.896C>G) is classified Uncertain significance in PRSS56 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-19). AlphaMissense: likely benign (0.1054); Very rare (popmax 0.0073%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PRSS56 p.Pro299Arg (c.896C>G)?

PRSS56 p.Pro299Arg (c.896C>G) is associated with Inborn genetic diseases (ClinVar).

How common is PRSS56 p.Pro299Arg (c.896C>G) in the general population?

PRSS56 p.Pro299Arg (c.896C>G) is very rare (popmax 0.0073%, nfe) (gnomAD).

What do computational predictors say about PRSS56 p.Pro299Arg (c.896C>G)?

AlphaMissense predicts likely benign (score 0.1054) — an in-silico prediction, not a clinical call.

PRSS56 p.Pro299Arg

c.896C>G · VCV3939191

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1054 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0073%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1054	likely benign
SaProt	LLR -10.26	damaging
⇒ SaProt calls this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 1.7, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 2,443 bp · p 0.05 · regional, not allelic
Overall
CADD	20.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; SaProt is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0073% European (non-Finnish) · 83/1,137,438 alleles

Filtering AF 0.00601% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00553%

Overall 0.00587% 89/1,516,324 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0073%	13,704
Remaining individualsnot grpmax-eligible	0.00508%	19,699
African / African-American	0.00413%	24,192

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.Pro299Arg
Coding: c.896C>G
MANE Select: NM_001195129
Type: single nucleotide variant
Location: chr2:232523462 (GRCh38)
Gene constraint: LOEUF 1.11 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.35
Residue 299: the peptidase s1 domain

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.Pro299Thr 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
PRSS56 p.Pro544Leu 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-pro299arg (accessed [today's date]).

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