Is SPP2 p.Arg133Pro (c.398G>C) pathogenic?

SPP2 p.Arg133Pro (c.398G>C) is classified Uncertain significance in SPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-08). AlphaMissense: likely pathogenic (0.6547); Very rare (popmax 0.00267%, afr).

How common is SPP2 p.Arg133Pro (c.398G>C) in the general population?

SPP2 p.Arg133Pro (c.398G>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about SPP2 p.Arg133Pro (c.398G>C)?

AlphaMissense predicts likely pathogenic (score 0.6547) — an in-silico prediction, not a clinical call.

SPP2 p.Arg133Pro

c.398G>C · rs376262894 · VCV1015618

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6547 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6547	likely pathogenic
REVEL	0.237	benign-leaning
SaProt	LLR -12.55	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.16	GERP -2.9
Regional constraint	o/e 1.02	unconstrained · MANE · 19 kb · p 0.75 · regional, not allelic
Overall
CADD	15.24	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 0.00267% African / African-American · 2/74,868 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,272 alleles · very rare exomes 1/1,461,120 · genomes 1/152,152 · 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: SPP2
Protein: p.Arg133Pro
Coding: c.398G>C
MANE Select: NM_006944
dbSNP: rs376262894
Type: single nucleotide variant
Location: chr2:234060433 (GRCh38)
Gene constraint: LOEUF 1.655 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.68

Full SPP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SPP2 p.Arg133Cys Uncertain significance ★★ ⚠ same residue
SPP2 p.Arg133His Conflicting classifications of pathogenicity ★ ⚠ same residue
SPP2 c.210+1G>A Uncertain significance ★★ same type
SPP2 c.500-1G>T Uncertain significance ★★ same type
SPP2 c.86-1G>T Uncertain significance ★★ same type
SPP2 p.Ala101Thr Uncertain significance ★★ ⚠ same type
SPP2 p.Arg161Ile Uncertain significance ★★ ⚠ same type
SPP2 p.Arg201Pro 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/spp2-p-arg133pro (accessed [today's date]).

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