Is SPP2 p.Ile174Val (c.520A>G) pathogenic?

SPP2 p.Ile174Val (c.520A>G) is classified Uncertain significance in SPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-13). AlphaMissense: likely benign (0.0723); Very rare (popmax 0.0011%, sas).

How common is SPP2 p.Ile174Val (c.520A>G) in the general population?

SPP2 p.Ile174Val (c.520A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about SPP2 p.Ile174Val (c.520A>G)?

AlphaMissense predicts likely benign (score 0.0723) — an in-silico prediction, not a clinical call.

SPP2 p.Ile174Val

c.520A>G · rs770675713 · VCV1948056

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0723 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0723	likely benign
REVEL	0.027	moderately benign-leaning
SaProt	LLR -6.09	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.016	GERP 0.81
Regional constraint	o/e 1.02	unconstrained · MANE · 19 kb · p 0.75 · regional, not allelic
Overall
CADD	9.12	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,068 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000558% 9/1,614,104 alleles · very rare exomes 9/1,461,798 · genomes 0/152,306 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,068
European (non-Finnish)	0.000678%	147,499

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.Ile174Val
Coding: c.520A>G
MANE Select: NM_006944
dbSNP: rs770675713
Type: single nucleotide variant
Location: chr2:234067244 (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-ile174val (accessed [today's date]).

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