Is SPP2 p.Ser38Phe (c.113C>T) pathogenic?

SPP2 p.Ser38Phe (c.113C>T) is classified Likely benign in SPP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.1827); Rare (popmax 0.909%, nfe).

How common is SPP2 p.Ser38Phe (c.113C>T) in the general population?

SPP2 p.Ser38Phe (c.113C>T) is rare (popmax 0.909%, nfe) (gnomAD).

What do computational predictors say about SPP2 p.Ser38Phe (c.113C>T)?

AlphaMissense predicts likely benign (score 0.1827) — an in-silico prediction, not a clinical call.

SPP2 p.Ser38Phe

c.113C>T · rs34347825 · VCV781690

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1827 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.909%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1827	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -8.74	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 0.33	GERP 3.3
Regional constraint	o/e 1.02	unconstrained · MANE · 19 kb · p 0.75 · regional, not allelic
Overall
CADD	15.35	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 0.909% European (non-Finnish) · 10,724/1,179,944 alleles

Filtering AF 0.894% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.888%

Overall 0.752% 12,134/1,614,016 alleles · rare exomes 11,192/1,461,732 · genomes 942/152,284 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.909%	110
Admixed American	0.882%	113
Remaining individualsnot grpmax-eligible	0.725%	138
Finnishnot grpmax-eligible	0.43%	233
Middle Eastern	0.281%	356
African / African-American	0.129%	774
Ashkenazi Jewishnot grpmax-eligible	0.0845%	1,184
South Asian	0.0154%	6,505

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.Ser38Phe
Coding: c.113C>T
MANE Select: NM_006944
dbSNP: rs34347825
Type: single nucleotide variant
Location: chr2:234050998 (GRCh38)
Gene constraint: LOEUF 1.655 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.68
Residue 38: a UniProt-annotated variant site (in)

Full SPP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SPP2 p.Ser38Ala 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
SPP2 p.Arg201Pro 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-ser38phe (accessed [today's date]).

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