Is SPP2 p.Pro58Leu (c.173C>T) pathogenic?

SPP2 p.Pro58Leu (c.173C>T) is classified Conflicting classifications of pathogenicity in SPP2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-05-05). AlphaMissense: likely benign (0.252); Ultra-rare (popmax 0.0165%, mid); Associated with inherited retinal dystrophy.

What condition is associated with SPP2 p.Pro58Leu (c.173C>T)?

SPP2 p.Pro58Leu (c.173C>T) is associated with inherited retinal dystrophy (ClinVar).

How common is SPP2 p.Pro58Leu (c.173C>T) in the general population?

SPP2 p.Pro58Leu (c.173C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about SPP2 p.Pro58Leu (c.173C>T)?

AlphaMissense predicts likely benign (score 0.252) — an in-silico prediction, not a clinical call.

SPP2 p.Pro58Leu

c.173C>T · rs143082886 · VCV1055065

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.252 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.252	likely benign
REVEL	0.147	moderately benign-leaning
SaProt	LLR -9.15	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 1.7	GERP 5.2, phastCons 0.28
Regional constraint	o/e 1.02	unconstrained · MANE · 19 kb · p 0.75 · regional, not allelic
Overall
CADD	22.9	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 0.0165% Middle Eastern · 1/6,076 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00409% 66/1,613,764 alleles · ultra-rare exomes 59/1,461,692 · genomes 7/152,072 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,076
Remaining individualsnot grpmax-eligible	0.0096%	10,413
African / African-American	0.00801%	12,479
European (non-Finnish)	0.00407%	24,581
South Asian	0.00329%	30,359
East Asian	0.00223%	44,872
Finnishnot grpmax-eligible	0.00156%	64,006

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.Pro58Leu
Coding: c.173C>T
MANE Select: NM_006944
dbSNP: rs143082886
Type: single nucleotide variant
Location: chr2:234051058 (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

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SPP2 p.Pro58= Likely benign ★★ same residue
SPP2 p.Tyr197Ter Uncertain significance ★★ same condition
SPP2 c.*2G>A Benign/Likely benign ★★ same condition
SPP2 p.Asp36Glu Benign ★★ same condition
SPP2 p.Thr90= Benign ★★ same condition
SPP2 p.Arg133His Conflicting classifications of pathogenicity ★ ⚠ same condition
SPP2 p.Arg62Gly Uncertain significance ★ same condition
SPP2 p.Arg93Lys Conflicting classifications of pathogenicity ★ ⚠ same condition

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-pro58leu (accessed [today's date]).

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