Is TSPYL6 p.Trp330Cys (c.990G>T) pathogenic?

TSPYL6 p.Trp330Cys (c.990G>T) is classified Uncertain significance in TSPYL6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-14). AlphaMissense: likely pathogenic (0.9429); Ultra-rare (popmax 0.0147%, nfe).

How common is TSPYL6 p.Trp330Cys (c.990G>T) in the general population?

TSPYL6 p.Trp330Cys (c.990G>T) is ultra-rare (popmax 0.0147%, nfe) (gnomAD).

What do computational predictors say about TSPYL6 p.Trp330Cys (c.990G>T)?

AlphaMissense predicts likely pathogenic (score 0.9429) — an in-silico prediction, not a clinical call.

TSPYL6 p.Trp330Cys

c.990G>T · rs368002272 · VCV3183919

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9429 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9429	likely pathogenic
REVEL	0.419	indeterminate
SaProt	LLR -12.81	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 2.9	GERP 1.9, phastCons 0.28
Regional constraint	o/e 1.32	unconstrained · MANE · 1,229 bp · p 3.7e-13 · regional, not allelic
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0147% European (non-Finnish) · 174/1,180,034 alleles

Filtering AF 0.0129% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0123%

Overall 0.011% 178/1,614,020 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0147%	6,782
Remaining individualsnot grpmax-eligible	0.0064%	15,620

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: TSPYL6
Protein: p.Trp330Cys
Coding: c.990G>T
MANE Select: NM_138448 · reported on NM_001003937
dbSNP: rs368002272
Type: single nucleotide variant
Location: chr2:54255162 (GRCh38)

Full TSPYL6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/tspyl6-p-trp330cys (accessed [today's date]).

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