Is SPNS2 p.Ala331Ser (c.991G>T) pathogenic?

SPNS2 p.Ala331Ser (c.991G>T) is classified Uncertain significance in SPNS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: likely benign (0.1759); Very rare (popmax 0.0011%, sas).

How common is SPNS2 p.Ala331Ser (c.991G>T) in the general population?

SPNS2 p.Ala331Ser (c.991G>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about SPNS2 p.Ala331Ser (c.991G>T)?

AlphaMissense predicts likely benign (score 0.1759) — an in-silico prediction, not a clinical call.

SPNS2 p.Ala331Ser

c.991G>T · VCV4173869

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1759 · 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	0.1759	likely benign
REVEL	0.242	benign-leaning
SaProt	LLR -7.23	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 9.8	GERP 0.49, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 4,393 bp · p 4.1e-10 · regional, not allelic
Overall
CADD	24.6	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

Overall 6.2e-05% 1/1,613,380 alleles · very rare exomes 1/1,461,070 · genomes 0/152,310 · joint denominator

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.Ala331Ser
Coding: c.991G>T
MANE Select: NM_001124758
Type: single nucleotide variant
Location: chr17:4533032 (GRCh38)
Gene constraint: LOEUF 0.958 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.85 · 18 PDB
Residue 331: an α-helix

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

Similar variants

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
SPNS2 c.1443+27C>A Benign ★★ same type
SPNS2 c.1443+28A>G 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-ala331ser (accessed [today's date]).

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