Is SPP2 p.Arg93Lys (c.278G>A) pathogenic?

SPP2 p.Arg93Lys (c.278G>A) is classified Conflicting classifications of pathogenicity in SPP2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-10-01). AlphaMissense: likely benign (0.1038); Very rare (popmax 0.00223%, eas); Associated with inherited retinal dystrophy.

What condition is associated with SPP2 p.Arg93Lys (c.278G>A)?

SPP2 p.Arg93Lys (c.278G>A) is associated with inherited retinal dystrophy (ClinVar).

How common is SPP2 p.Arg93Lys (c.278G>A) in the general population?

SPP2 p.Arg93Lys (c.278G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about SPP2 p.Arg93Lys (c.278G>A)?

AlphaMissense predicts likely benign (score 0.1038) — an in-silico prediction, not a clinical call.

SPP2 p.Arg93Lys

c.278G>A · rs2125455747 · VCV1422054

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1038 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.1038	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -5.97	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 1.8	GERP 3.3, phastCons 0.98
Regional constraint	o/e 1.02	unconstrained · MANE · 19 kb · p 0.75 · regional, not allelic
Overall
CADD	15.61	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 0.00223% East Asian · 1/44,874 alleles

Overall 6.2e-05% 1/1,614,116 alleles · very rare exomes 1/1,461,792 · genomes 0/152,324 · 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.Arg93Lys
Coding: c.278G>A
MANE Select: NM_006944
dbSNP: rs2125455747
Type: single nucleotide variant
Location: chr2:234058903 (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.Arg93Gly Uncertain significance ★★ ⚠ same residue
SPP2 p.Arg93Ser Uncertain significance ★ ⚠ same residue
SPP2 p.Arg93= 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

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-arg93lys (accessed [today's date]).

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