Is SPP2 p.Ser53Cys (c.158C>G) pathogenic?

SPP2 p.Ser53Cys (c.158C>G) is classified Uncertain significance in SPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-27). AlphaMissense: ambiguous (0.4984); Ultra-rare (popmax 0.084%, afr).

How common is SPP2 p.Ser53Cys (c.158C>G) in the general population?

SPP2 p.Ser53Cys (c.158C>G) is ultra-rare (popmax 0.084%, afr) (gnomAD).

What do computational predictors say about SPP2 p.Ser53Cys (c.158C>G)?

AlphaMissense predicts ambiguous (score 0.4984) — an in-silico prediction, not a clinical call.

SPP2 p.Ser53Cys

c.158C>G · rs144683165 · VCV960366

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4984 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.084%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4984	ambiguous
REVEL	0.185	benign-leaning
SaProt	LLR -10.69	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.8	GERP 5.2, phastCons 0.51
Regional constraint	o/e 1.02	unconstrained · MANE · 19 kb · p 0.75 · regional, not allelic
Overall
CADD	24.3	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 0.084% African / African-American · 63/75,038 alleles

Filtering AF 0.0673% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0613%

Overall 0.00496% 80/1,614,014 alleles · ultra-rare exomes 44/1,461,726 · genomes 36/152,288 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.084%	1,191
Admixed American	0.015%	6,665
Remaining individualsnot grpmax-eligible	0.0112%	8,929
European (non-Finnish)	8.48e-05%	1,179,935

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.Ser53Cys
Coding: c.158C>G
MANE Select: NM_006944
dbSNP: rs144683165
Type: single nucleotide variant
Location: chr2:234051043 (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 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.Arg133Cys Uncertain significance ★★ ⚠ same type
SPP2 p.Arg161Ile Uncertain significance ★★ ⚠ same type
SPP2 p.Arg201Pro Uncertain significance ★★ ⚠ same type
SPP2 p.Arg62Gln 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-ser53cys (accessed [today's date]).

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