Is TOP6BL p.Ser336Pro (c.1006T>C) pathogenic?

TOP6BL p.Ser336Pro (c.1006T>C) is classified Uncertain significance in TOP6BL (ClinVar, Single submitter, 2 submitters; last evaluated 2019-09-30). AlphaMissense: likely pathogenic (0.9136); Ultra-rare (popmax 0.0137%, amr); Associated with hydatidiform mole, recurrent, 4.

What condition is associated with TOP6BL p.Ser336Pro (c.1006T>C)?

TOP6BL p.Ser336Pro (c.1006T>C) is associated with hydatidiform mole, recurrent, 4 (ClinVar).

How common is TOP6BL p.Ser336Pro (c.1006T>C) in the general population?

TOP6BL p.Ser336Pro (c.1006T>C) is ultra-rare (popmax 0.0137%, amr) (gnomAD).

How is Hydatidiform mole inherited?

Typically Autosomal recessive, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TOP6BL p.Ser336Pro (c.1006T>C)?

AlphaMissense predicts likely pathogenic (score 0.9136) — an in-silico prediction, not a clinical call.

TOP6BL p.Ser336Pro

c.1006T>C · rs1449401018 · VCV627626

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9136 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0137%, amr)

Conditions

hydatidiform mole, recurrent, 4

Computational evidence

Protein change
AlphaMissense	0.9136	likely pathogenic · top 1% in TOP6BL
REVEL	0.309	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 84 kb · p 0.92 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S401P vs ClinVar S336P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0137% Admixed American · 7/51,086 alleles

Filtering AF 0.00638% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00454%

Overall 0.000451% 7/1,553,052 alleles · ultra-rare exomes 6/1,400,868 · genomes 1/152,184 · 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: TOP6BL
Protein: p.Ser336Pro
Coding: c.1006T>C
MANE Select: NM_001302084
dbSNP: rs1449401018
Type: single nucleotide variant
Location: chr11:66822606 (GRCh38)
Structure: AlphaFold pLDDT 68.14

Full TOP6BL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hydatidiform mole, recurrent, 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hydatidiform mole (Orphanet):

Inheritance: Autosomal recessive, Not applicable
Onset: Adolescent, Adult

Similar variants

TOP6BL p.Lys425fs Likely pathogenic ★ same condition
TOP6BL p.Glu96Ter Uncertain significance ★ same condition
TOP6BL c.-30+3538A>G Uncertain significance ★ ⚠ same type
TOP6BL p.Ala406Thr Uncertain significance ★ ⚠ same type
TOP6BL p.Arg374Cys Uncertain significance ★ ⚠ same type
TOP6BL p.Asp232His Uncertain significance ★ ⚠ same type
TOP6BL p.His131Asn Uncertain significance ★ same type
TOP6BL p.Met352Arg 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/top6bl-p-ser336pro (accessed [today's date]).

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