Is SPP2 p.Cys92Arg (c.274T>C) pathogenic?

SPP2 p.Cys92Arg (c.274T>C) is classified Conflicting classifications of pathogenicity in SPP2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-01-23). AlphaMissense: likely pathogenic (0.9777); Ultra-rare (popmax 0.0735%, eas); Associated with inherited retinal dystrophy.

What condition is associated with SPP2 p.Cys92Arg (c.274T>C)?

SPP2 p.Cys92Arg (c.274T>C) is associated with inherited retinal dystrophy (ClinVar).

How common is SPP2 p.Cys92Arg (c.274T>C) in the general population?

SPP2 p.Cys92Arg (c.274T>C) is ultra-rare (popmax 0.0735%, eas) (gnomAD).

What do computational predictors say about SPP2 p.Cys92Arg (c.274T>C)?

AlphaMissense predicts likely pathogenic (score 0.9777) — an in-silico prediction, not a clinical call.

SPP2 p.Cys92Arg

c.274T>C · rs763549452 · VCV1046799

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9777 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0735%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.9777	likely pathogenic · top 1% in SPP2
REVEL	0.811	moderately pathogenic-leaning
SaProt	LLR -12.40	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 5.3, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 19 kb · p 0.75 · regional, not allelic
Overall
CADD	26.9	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 0.0735% East Asian · 33/44,886 alleles

Filtering AF 0.0538% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.047%

Overall 0.00204% 33/1,613,984 alleles · ultra-rare exomes 32/1,461,796 · genomes 1/152,188 · 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.Cys92Arg
Coding: c.274T>C
MANE Select: NM_006944
dbSNP: rs763549452
Type: single nucleotide variant
Location: chr2:234058899 (GRCh38)
Gene constraint: LOEUF 1.655 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.68
Residue 92: a disulfide bond

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.Cys92Tyr Uncertain significance ★ ⚠ 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-cys92arg (accessed [today's date]).

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