Is PRSS56 p.Pro87Ala (c.259C>G) pathogenic?

PRSS56 p.Pro87Ala (c.259C>G) is classified Uncertain significance in PRSS56 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-16). AlphaMissense: likely benign (0.0638); Ultra-rare (popmax 0.0404%, nfe); Associated with isolated microphthalmia 6.

What condition is associated with PRSS56 p.Pro87Ala (c.259C>G)?

PRSS56 p.Pro87Ala (c.259C>G) is associated with isolated microphthalmia 6 (ClinVar).

How common is PRSS56 p.Pro87Ala (c.259C>G) in the general population?

PRSS56 p.Pro87Ala (c.259C>G) is ultra-rare (popmax 0.0404%, nfe) (gnomAD).

What do computational predictors say about PRSS56 p.Pro87Ala (c.259C>G)?

AlphaMissense predicts likely benign (score 0.0638) — an in-silico prediction, not a clinical call.

PRSS56 p.Pro87Ala

c.259C>G · rs547205012 · VCV1397321

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0638 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0404%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Conditions

isolated microphthalmia 6

Computational evidence

Protein change
AlphaMissense	0.0638	likely benign
SaProt	LLR -5.16	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 0.41	GERP -1.5, phastCons 0.006
Regional constraint	o/e 1.00	unconstrained · MANE · 2,232 bp · p 0.94 · regional, not allelic
Overall
CADD	13.34	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 0.0404% European (non-Finnish) · 450/1,115,042 alleles

Filtering AF 0.0372% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.036%

Overall 0.0332% 489/1,472,830 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.045%	2,223
European (non-Finnish)grpmax	0.0404%	2,478
Remaining individualsnot grpmax-eligible	0.0316%	3,169
Admixed American	0.0164%	6,092
African / African-American	0.00425%	23,544

Ashkenazi Jewish 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.Pro87Ala
Coding: c.259C>G
MANE Select: NM_001195129
dbSNP: rs547205012
Type: single nucleotide variant
Location: chr2:232521973 (GRCh38)
Gene constraint: LOEUF 1.11 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.35
Residue 87: the 'disordered' region

Full PRSS56 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

isolated microphthalmia 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PRSS56 p.Ala502Thr Uncertain significance ★★ ⚠ same condition
PRSS56 p.Ala57Val Uncertain significance ★★ ⚠ same condition
PRSS56 p.Ala600Thr Uncertain significance ★★ ⚠ same condition
PRSS56 p.Arg247Cys Uncertain significance ★★ ⚠ same condition
PRSS56 p.Asp254Asn 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-pro87ala (accessed [today's date]).

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