Is PRTN3 p.Arg235Pro (c.704G>C) pathogenic?

PRTN3 p.Arg235Pro (c.704G>C) is classified Uncertain significance in PRTN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-17). AlphaMissense: likely pathogenic (0.5999); Ultra-rare (popmax 0.0286%, amr).

How common is PRTN3 p.Arg235Pro (c.704G>C) in the general population?

PRTN3 p.Arg235Pro (c.704G>C) is ultra-rare (popmax 0.0286%, amr) (gnomAD).

What do computational predictors say about PRTN3 p.Arg235Pro (c.704G>C)?

AlphaMissense predicts likely pathogenic (score 0.5999) — an in-silico prediction, not a clinical call.

PRTN3 p.Arg235Pro

c.704G>C · VCV3939250

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5999 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0286%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5999	likely pathogenic
REVEL	0.264	benign-leaning
SaProt	LLR -8.67	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.93 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.2	GERP -3
Regional constraint	o/e 1.05	unconstrained · MANE · 6,957 bp · p 0.33 · regional, not allelic
Overall
CADD	15.64	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0286% Admixed American · 17/59,360 alleles

Filtering AF 0.0182% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0149%

Overall 0.00112% 18/1,608,236 alleles · ultra-rare exomes 16/1,455,984 · genomes 2/152,252 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0286%	3,492
European (non-Finnish)	8.49e-05%	1,177,346

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: PRTN3
Protein: p.Arg235Pro
Coding: c.704G>C
MANE Select: NM_002777
Type: single nucleotide variant
Location: chr19:847902 (GRCh38)
Gene constraint: LOEUF 1.885 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.06 · 2 PDB
Residue 235: the peptidase s1 domain; a β-strand

Full PRTN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PRTN3 p.Arg235Trp Uncertain significance ★ ⚠ same residue
PRTN3 p.Arg4Gln Likely benign ★★ same type
PRTN3 p.Val66= Benign/Likely benign ★★ same type
PRTN3 p.Ala103Val Uncertain significance ★ ⚠ same type
PRTN3 p.Arg159His Uncertain significance ★ ⚠ same type
PRTN3 p.Arg227Cys Uncertain significance ★ same type
PRTN3 p.Arg227His Uncertain significance ★ ⚠ same type
PRTN3 p.Arg248His Uncertain significance ★ ⚠ same type

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/prtn3-p-arg235pro (accessed [today's date]).

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