Is SPP2 p.Phe151Ser (c.452T>C) pathogenic?

SPP2 p.Phe151Ser (c.452T>C) is classified Likely benign in SPP2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-08). AlphaMissense: ambiguous (0.3603); Rare (popmax 0.245%, afr).

How common is SPP2 p.Phe151Ser (c.452T>C) in the general population?

SPP2 p.Phe151Ser (c.452T>C) is rare (popmax 0.245%, afr) (gnomAD).

What do computational predictors say about SPP2 p.Phe151Ser (c.452T>C)?

AlphaMissense predicts ambiguous (score 0.3603) — an in-silico prediction, not a clinical call.

SPP2 p.Phe151Ser

c.452T>C · rs139040392 · VCV1114155

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3603 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.245%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3603	ambiguous
REVEL	0.268	benign-leaning
SaProt	LLR -5.09	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 5.2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 19 kb · p 0.75 · regional, not allelic
Overall
CADD	22.8	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 0.245% African / African-American · 184/75,034 alleles

Filtering AF 0.216% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.205%

Overall 0.0169% 273/1,612,554 alleles · rare exomes 148/1,460,222 · genomes 125/152,332 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.245%	408
Admixed American	0.0467%	2,142
Remaining individualsnot grpmax-eligible	0.0208%	4,806
European (non-Finnish)	0.00407%	24,576

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.Phe151Ser
Coding: c.452T>C
MANE Select: NM_006944
dbSNP: rs139040392
Type: single nucleotide variant
Location: chr2:234066540 (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-phe151ser (accessed [today's date]).

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