Is SPIN1 p.Ala126Ser (c.376G>T) pathogenic?

SPIN1 p.Ala126Ser (c.376G>T) is classified Uncertain significance in SPIN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-19). AlphaMissense: likely benign (0.0875); Very rare (popmax 0.000428%, nfe).

How common is SPIN1 p.Ala126Ser (c.376G>T) in the general population?

SPIN1 p.Ala126Ser (c.376G>T) is very rare (popmax 0.000428%, nfe) (gnomAD).

What do computational predictors say about SPIN1 p.Ala126Ser (c.376G>T)?

AlphaMissense predicts likely benign (score 0.0875) — an in-silico prediction, not a clinical call.

SPIN1 p.Ala126Ser

c.376G>T · VCV4173699

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0875 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000428%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0875	likely benign
REVEL	0.061	moderately benign-leaning
SaProt	LLR -6.23	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.069, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 5,725 bp · p 0.0023 · regional, not allelic
Overall
CADD	22.9	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 0.000428% European (non-Finnish) · 5/1,167,708 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000315% 5/1,585,716 alleles · very rare exomes 2/1,435,240 · genomes 3/150,476 · 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: SPIN1
Protein: p.Ala126Ser
Coding: c.376G>T
MANE Select: NM_006717
Type: single nucleotide variant
Location: chr9:88468392 (GRCh38)
Gene constraint: LOEUF 0.253 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 82.14 · 20 PDB
Residue 126: an α-helix

Full SPIN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SPIN1 p.Ala119Val Uncertain significance ★ ⚠ same type
SPIN1 p.Arg117Gly Uncertain significance ★ ⚠ same type
SPIN1 p.Arg37Trp Uncertain significance ★ ⚠ same type
SPIN1 p.Asn163Ser Uncertain significance ★ ⚠ same type
SPIN1 p.Asp198Tyr Uncertain significance ★ ⚠ same type
SPIN1 p.His127Arg Uncertain significance ★ ⚠ same type
SPIN1 p.Pro194Ser Uncertain significance ★ same type
SPIN1 p.Val82Leu 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/spin1-p-ala126ser (accessed [today's date]).

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