Is SPP2 p.Thr9Met (c.26C>T) pathogenic?

SPP2 p.Thr9Met (c.26C>T) is classified Conflicting classifications of pathogenicity in SPP2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0762); Ultra-rare (popmax 0.0164%, mid).

How common is SPP2 p.Thr9Met (c.26C>T) in the general population?

SPP2 p.Thr9Met (c.26C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about SPP2 p.Thr9Met (c.26C>T)?

AlphaMissense predicts likely benign (score 0.0762) — an in-silico prediction, not a clinical call.

SPP2 p.Thr9Met

c.26C>T · rs145529777 · VCV971275

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0762 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0762	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -4.99	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 -3	GERP -5.6, phastCons 0.16
Regional constraint	o/e 1.02	unconstrained · MANE · 19 kb · p 0.75 · regional, not allelic
Overall
CADD	1.287	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 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00353% 57/1,613,818 alleles · ultra-rare exomes 53/1,461,670 · genomes 4/152,148 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.024%	4,165
Middle Easterngrpmax	0.0164%	6,080
East Asian	0.0134%	7,482
Admixed American	0.00667%	15,000
European (non-Finnish)	0.00237%	42,138
South Asian	0.0022%	45,529
African / African-American	0.00134%	74,904

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr9Met
Coding: c.26C>T
MANE Select: NM_006944
dbSNP: rs145529777
Type: single nucleotide variant
Location: chr2:234050812 (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.Thr9Arg Uncertain significance ★★ ⚠ same residue
SPP2 p.Thr9= Likely benign ★★ 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.Arg133Cys Uncertain significance ★★ ⚠ same type
SPP2 p.Arg161Ile 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-thr9met (accessed [today's date]).

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