Is SETX p.Ala971Pro (c.2911G>C) pathogenic?

SETX p.Ala971Pro (c.2911G>C) is classified Uncertain significance in SETX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-16). AlphaMissense: ambiguous (0.3796); Very rare (popmax 8.48e-05%, nfe).

How common is SETX p.Ala971Pro (c.2911G>C) in the general population?

SETX p.Ala971Pro (c.2911G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about SETX p.Ala971Pro (c.2911G>C)?

AlphaMissense predicts ambiguous (score 0.3796) — an in-silico prediction, not a clinical call.

SETX p.Ala971Pro

c.2911G>C · VCV3731249

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3796 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3796	ambiguous
REVEL	0.418	indeterminate
SaProt	LLR -6.45	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4	GERP 0.77, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 3,399 bp · p 2.4e-06 · regional, not allelic
Overall
CADD	23.9	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 8.48e-05% European (non-Finnish) · 1/1,179,844 alleles

Overall 6.2e-05% 1/1,613,774 alleles · very rare exomes 1/1,461,476 · genomes 0/152,298 · 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: SETX
Protein: p.Ala971Pro
Coding: c.2911G>C
MANE Select: NM_015046
Type: single nucleotide variant
Location: chr9:132328687 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93

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

Similar variants

SETX p.Arg111Ter Pathogenic ★★ same type
SETX p.Arg1363Ter Pathogenic ★★ same type
SETX p.Arg1606Ter Pathogenic ★★ same type
SETX p.Arg1778Ter Pathogenic/Likely pathogenic ★★ same type
SETX p.Arg2098Ter Pathogenic ★★ same type
SETX p.Arg332Trp Pathogenic/Likely pathogenic ★★ same type
SETX p.Arg778Ter Pathogenic/Likely pathogenic ★★ same type
SETX p.Gln1695Ter Pathogenic/Likely pathogenic ★★ 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/setx-p-ala971pro (accessed [today's date]).

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