Is PTPRS p.Pro1057Ser (c.3169C>T) pathogenic?

PTPRS p.Pro1057Ser (c.3169C>T) is classified Uncertain significance in PTPRS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-17). AlphaMissense: ambiguous (0.5623); Very rare (popmax 0.000254%, nfe).

How common is PTPRS p.Pro1057Ser (c.3169C>T) in the general population?

PTPRS p.Pro1057Ser (c.3169C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about PTPRS p.Pro1057Ser (c.3169C>T)?

AlphaMissense predicts ambiguous (score 0.5623) — an in-silico prediction, not a clinical call.

PTPRS p.Pro1057Ser

c.3169C>T · rs768857484 · VCV2327144

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5623 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5623	ambiguous
REVEL	0.287	benign-leaning
SaProt	LLR -8.66	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 1,149 bp · p 0.12 · regional, not allelic
Overall
CADD	22.6	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 0.000254% European (non-Finnish) · 3/1,179,984 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,838 alleles · very rare exomes 2/1,461,678 · genomes 1/152,160 · joint denominator

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: PTPRS
Protein: p.Pro1057Ser
Coding: c.3169C>T
MANE Select: NM_002850
dbSNP: rs768857484
Type: single nucleotide variant
Location: chr19:5222155 (GRCh38)
Gene constraint: LOEUF 0.378 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.94 · 6 PDB
Residue 1057: the fibronectin type-iii 8 domain

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

Similar variants

PTPRS p.Arg1572Trp Uncertain significance ★★ ⚠ same type
PTPRS p.Ala87= Benign ★★ same type
PTPRS p.Ala972= Benign ★★ same type
PTPRS p.Asn1737= Benign ★★ same type
PTPRS p.Glu165= Likely benign ★★ same type
PTPRS p.Gly1107= Likely benign ★★ same type
PTPRS p.His1642= Benign ★★ same type
PTPRS p.Ile1741= Benign ★★ 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/ptprs-p-pro1057ser (accessed [today's date]).

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