Is S1PR2 p.Pro265Arg (c.794C>G) pathogenic?

S1PR2 p.Pro265Arg (c.794C>G) is classified Uncertain significance in S1PR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-09). AlphaMissense: likely benign (0.1015); Ultra-rare (popmax 0.0878%, sas).

How common is S1PR2 p.Pro265Arg (c.794C>G) in the general population?

S1PR2 p.Pro265Arg (c.794C>G) is ultra-rare (popmax 0.0878%, sas) (gnomAD).

What do computational predictors say about S1PR2 p.Pro265Arg (c.794C>G)?

AlphaMissense predicts likely benign (score 0.1015) — an in-silico prediction, not a clinical call.

S1PR2 p.Pro265Arg

c.794C>G · VCV4537963

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1015 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0878%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1015	likely benign
REVEL	0.193	benign-leaning
SaProt	LLR -8.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 1,058 bp · p 8.2e-09 · regional, not allelic
Overall
CADD	22.4	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 0.0878% South Asian · 80/91,088 alleles

Filtering AF 0.0722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0666%

Overall 0.00592% 95/1,604,904 alleles · ultra-rare exomes 90/1,452,552 · genomes 5/152,352 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0878%	1,139
Middle Eastern	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.0064%	15,615
European (non-Finnish)	0.000847%	117,998

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: S1PR2
Protein: p.Pro265Arg
Coding: c.794C>G
MANE Select: NM_004230
Type: single nucleotide variant
Location: chr19:10224112 (GRCh38)
Gene constraint: LOEUF 0.834 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 82.73 · 2 PDB

Full S1PR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

S1PR2 p.Pro265Gln Uncertain significance ★ ⚠ same residue
S1PR2 p.Pro265Leu Uncertain significance ★ ⚠ same residue
S1PR2 p.Ala36Val Uncertain significance ★★ ⚠ same type
S1PR2 p.Ala77Thr Uncertain significance ★★ ⚠ same type
S1PR2 p.Ala77Val Uncertain significance ★★ ⚠ same type
S1PR2 p.Arg211His Uncertain significance ★★ ⚠ same type
S1PR2 p.Arg217His Uncertain significance ★★ ⚠ same type
S1PR2 p.Arg293Trp 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/s1pr2-p-pro265arg (accessed [today's date]).

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