Is PRSS56 p.Ala41= (c.123G>A) pathogenic?

PRSS56 p.Ala41= (c.123G>A) is classified Likely benign in PRSS56 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-19). Ultra-rare (popmax 0.0981%, amr); Associated with isolated microphthalmia 6.

What condition is associated with PRSS56 p.Ala41= (c.123G>A)?

PRSS56 p.Ala41= (c.123G>A) is associated with isolated microphthalmia 6 (ClinVar).

How common is PRSS56 p.Ala41= (c.123G>A) in the general population?

PRSS56 p.Ala41= (c.123G>A) is ultra-rare (popmax 0.0981%, amr) (gnomAD).

PRSS56 p.Ala41=

c.123G>A · rs959302495 · VCV1603498

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0981%, amr)

Conditions

isolated microphthalmia 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.3	GERP -2.6
Overall
CADD	3.728	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0981% Admixed American · 50/50,986 alleles

Filtering AF 0.0763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0687%

Overall 0.00996% 153/1,536,030 alleles · ultra-rare exomes 144/1,383,784 · genomes 9/152,246 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0981%	1,020
Remaining individualsnot grpmax-eligible	0.00833%	11,999
European (non-Finnish)	0.00828%	12,073
East Asian	0.00489%	20,461
African / African-American	0.00137%	73,060

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.Ala41=
Coding: c.123G>A
MANE Select: NM_001195129
dbSNP: rs959302495
Type: single nucleotide variant
Location: chr2:232521346 (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

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

Similar variants

PRSS56 p.Ala41Val Uncertain significance ★ ⚠ same residue
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

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-ala41 (accessed [today's date]).

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