Is SPNS2 p.Pro71Ser (c.211C>T) pathogenic?

SPNS2 p.Pro71Ser (c.211C>T) is classified Uncertain significance in SPNS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-01). AlphaMissense: likely benign (0.0726); Ultra-rare (popmax 0.0122%, amr).

How common is SPNS2 p.Pro71Ser (c.211C>T) in the general population?

SPNS2 p.Pro71Ser (c.211C>T) is ultra-rare (popmax 0.0122%, amr) (gnomAD).

What do computational predictors say about SPNS2 p.Pro71Ser (c.211C>T)?

AlphaMissense predicts likely benign (score 0.0726) — an in-silico prediction, not a clinical call.

SPNS2 p.Pro71Ser

c.211C>T · VCV3961215

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0726 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0726	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -5.72	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 1.2	GERP -2, phastCons 0.99
Regional constraint	o/e 0.81	unconstrained · MANE · 33 kb · p 0.00016 · regional, not allelic
Overall
CADD	16.32	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 0.0122% Admixed American · 5/40,934 alleles

Filtering AF 0.00479% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00308%

Overall 0.000753% 11/1,461,382 alleles · ultra-rare exomes 10/1,309,942 · genomes 1/151,440 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0122%	8,187
African / African-American	0.00296%	33,800
Remaining individualsnot grpmax-eligible	0.00177%	56,376
European (non-Finnish)	0.00027%	370,822

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: SPNS2
Protein: p.Pro71Ser
Coding: c.211C>T
MANE Select: NM_001124758
Type: single nucleotide variant
Location: chr17:4499258 (GRCh38)
Gene constraint: LOEUF 0.958 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.85 · 18 PDB
Residue 71: the 'disordered' region

Full SPNS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SPNS2 p.Pro71Thr Uncertain significance ★ ⚠ same residue
SPNS2 p.Pro71= Likely benign ★ same residue
SPNS2 p.Ala401Thr Uncertain significance ★★ ⚠ same type
SPNS2 p.Ala545Thr Uncertain significance ★★ ⚠ same type
SPNS2 c.1279-152G>A Benign ★★ same type
SPNS2 c.1344+66C>T Benign ★★ same type
SPNS2 c.1345-58A>G Benign ★★ same type
SPNS2 c.1345-89G>A Benign ★★ 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/spns2-p-pro71ser (accessed [today's date]).

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