Is PTPRS p.Ser663Pro (c.1987T>C) pathogenic?

PTPRS p.Ser663Pro (c.1987T>C) is classified Uncertain significance in PTPRS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-28). AlphaMissense: likely benign (0.1677); Very rare (popmax 0.00167%, amr).

How common is PTPRS p.Ser663Pro (c.1987T>C) in the general population?

PTPRS p.Ser663Pro (c.1987T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about PTPRS p.Ser663Pro (c.1987T>C)?

AlphaMissense predicts likely benign (score 0.1677) — an in-silico prediction, not a clinical call.

PTPRS p.Ser663Pro

c.1987T>C · VCV3428265

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1677 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1677	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -9.96	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.2	GERP -3.2, phastCons 0.9
Regional constraint	o/e 0.83	unconstrained · MANE · 17 kb · p 0.00034 · regional, not allelic
Overall
CADD	23.3	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 0.00167% Admixed American · 1/59,982 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000558% 9/1,612,632 alleles · very rare exomes 7/1,460,870 · genomes 2/151,762 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,982
African / African-American	0.00134%	74,758
European (non-Finnish)	0.000593%	168,555

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.Ser663Pro
Coding: c.1987T>C
MANE Select: NM_002850
Type: single nucleotide variant
Location: chr19:5231478 (GRCh38)
Gene constraint: LOEUF 0.378 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.94 · 6 PDB
Residue 663: the fibronectin type-iii 4 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-ser663pro (accessed [today's date]).

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