Is PRSS56 p.Pro355His (c.1064C>A) pathogenic?

PRSS56 p.Pro355His (c.1064C>A) is classified Uncertain significance in PRSS56 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-17). AlphaMissense: likely benign (0.1199); Ultra-rare (popmax 0.0698%, afr); Associated with Inborn genetic diseases.

What condition is associated with PRSS56 p.Pro355His (c.1064C>A)?

PRSS56 p.Pro355His (c.1064C>A) is associated with Inborn genetic diseases (ClinVar).

How common is PRSS56 p.Pro355His (c.1064C>A) in the general population?

PRSS56 p.Pro355His (c.1064C>A) is ultra-rare (popmax 0.0698%, afr) (gnomAD).

What do computational predictors say about PRSS56 p.Pro355His (c.1064C>A)?

AlphaMissense predicts likely benign (score 0.1199) — an in-silico prediction, not a clinical call.

PRSS56 p.Pro355His

c.1064C>A · VCV3310737

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1199 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0698%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1199	likely benign
SaProt	LLR -7.40	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 0.27	GERP 1.6
Regional constraint	o/e 1.09	unconstrained · MANE · 2,443 bp · p 0.05 · regional, not allelic
Overall
CADD	15.64	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 0.0698% African / African-American · 51/73,088 alleles

Filtering AF 0.0545% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.049%

Overall 0.00561% 86/1,533,642 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.768%	130
African / African-Americangrpmax	0.0698%	1,433
Middle Eastern	0.0207%	4,820
Admixed American	0.00589%	16,987
East Asian	0.00489%	20,437
Remaining individualsnot grpmax-eligible	0.00334%	29,929
South Asian	0.00238%	41,978
European (non-Finnish)	0.00157%	63,692

Amish 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: PRSS56
Protein: p.Pro355His
Coding: c.1064C>A
MANE Select: NM_001195129
Type: single nucleotide variant
Location: chr2:232523823 (GRCh38)
Gene constraint: LOEUF 1.11 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.35

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.Pro355Leu 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-pro355his (accessed [today's date]).

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