Is SPP2 p.Arg181Trp (c.541C>T) pathogenic?

SPP2 p.Arg181Trp (c.541C>T) is classified Uncertain significance in SPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-23). AlphaMissense: likely benign (0.1172); Ultra-rare (popmax 0.0164%, mid).

How common is SPP2 p.Arg181Trp (c.541C>T) in the general population?

SPP2 p.Arg181Trp (c.541C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about SPP2 p.Arg181Trp (c.541C>T)?

AlphaMissense predicts likely benign (score 0.1172) — an in-silico prediction, not a clinical call.

SPP2 p.Arg181Trp

c.541C>T · rs375462993 · VCV956174

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1172 · 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	0.1172	likely benign
REVEL	0.19	benign-leaning
SaProt	LLR -8.24	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.48 · evaluated, not missing
Pangolin	Δ0.22	loss · gain 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP -0.067	GERP 2.4
Regional constraint	o/e 1.02	unconstrained · MANE · 19 kb · p 0.75 · regional, not allelic
Overall
CADD	22.3	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00896%

Overall 0.00942% 152/1,613,868 alleles · ultra-rare exomes 143/1,461,728 · genomes 9/152,140 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
European (non-Finnish)	0.0111%	9,007
African / African-American	0.0107%	9,363
South Asian	0.00769%	13,010
Remaining individualsnot grpmax-eligible	0.0064%	15,619
East Asian	0.00223%	44,876

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.Arg181Trp
Coding: c.541C>T
MANE Select: NM_006944
dbSNP: rs375462993
Type: single nucleotide variant
Location: chr2:234067265 (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.Arg181= Uncertain significance ★ same residue
SPP2 p.Arg181Gln Uncertain significance ★ ⚠ 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-arg181trp (accessed [today's date]).

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