Is TSPYL6 p.Arg136Ser (c.408G>T) pathogenic?

TSPYL6 p.Arg136Ser (c.408G>T) is classified Uncertain significance in TSPYL6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-28). AlphaMissense: likely benign (0.1474); Rare (popmax 0.113%, amr).

How common is TSPYL6 p.Arg136Ser (c.408G>T) in the general population?

TSPYL6 p.Arg136Ser (c.408G>T) is rare (popmax 0.113%, amr) (gnomAD).

What do computational predictors say about TSPYL6 p.Arg136Ser (c.408G>T)?

AlphaMissense predicts likely benign (score 0.1474) — an in-silico prediction, not a clinical call.

TSPYL6 p.Arg136Ser

c.408G>T · rs187843016 · VCV2341222

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1474 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.113%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1474	likely benign
REVEL	0.01	strongly benign-leaning
SaProt	LLR -5.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -2.6	GERP -2.3
Regional constraint	o/e 1.32	unconstrained · MANE · 1,229 bp · p 3.7e-13 · regional, not allelic
Overall
CADD	0.226	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 0.113% Admixed American · 68/60,032 alleles

Filtering AF 0.0916% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0838%

Overall 0.0148% 239/1,614,002 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.113%	883
Remaining individualsnot grpmax-eligible	0.0192%	5,209
European (non-Finnish)	0.0132%	7,564
African / African-American	0.004%	25,020

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.Arg136Ser
Coding: c.408G>T
MANE Select: NM_138448 · reported on NM_001003937
dbSNP: rs187843016
Type: single nucleotide variant
Location: chr2:54255744 (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-arg136ser (accessed [today's date]).

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